Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof

ABSTRACT

The present invention is directed to substituted 2-aryl-4-arylaminopyrimidine and analogs thereof, represented by the general Formula I: 
                         
wherein A, Ar 1 , Ar 2 , R 1  and R 3  are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. The compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

This is a divisional of U.S. Ser. No. 10/012,444 filed Dec. 12, 2001,now U.S. Pat. No. 6,716,851 which claims the benefit of U.S. ProvisionalApplication No. 60/254,581 filed Dec. 12, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to substituted 2-aryl-4-arylaminopyrimidines andanalogs, and the discovery that these compounds are activators ofcaspases and inducers of apoptosis. The invention also relates to theuse of these compounds as therapeutically effective anti-cancer agents.

2. Related Art

Organisms eliminate unwanted cells by a process variously known asregulated cell death, programmed cell death or apoptosis. Such celldeath occurs as a normal aspect of animal development as well as intissue homeostasis and aging (Glucksmann, A., Biol. Rev. CambridgePhilos. Soc. 26:59–86 (1951); Glucksmann, A., Archives de Biologie76:419–437 (1965); Ellis, et al., Dev. 112:591–603 (1991); Vaux, et al.,Cell 76:777–779 (1994)). Apoptosis regulates cell number, facilitatesmorphogenesis, removes harmful or otherwise abnormal cells andeliminates cells that have already performed their function.Additionally, apoptosis occurs in response to various physiologicalstresses, such as hypoxia or ischemia (PCT published applicationWO96/20721).

There are a number of morphological changes shared by cells experiencingregulated cell death, including plasma and nuclear membrane blebbing,cell shrinkage (condensation of nucleoplasm and cytoplasm), organellerelocalization and compaction, chromatin condensation and production ofapoptotic bodies (membrane enclosed particles containing intracellularmaterial) (Orrenius, S., J. Internal Medicine 237:529–536 (1995)).

Apoptosis is achieved through an endogenous mechanism of cellularsuicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowenand Lockshin, eds., Chapman and Hall (1981), pp. 9–34). A cell activatesits internally encoded suicide program as a result of either internal orexternal signals. The suicide program is executed through the activationof a carefully regulated genetic program (Wyllie, et al., Int. Rev. Cyt.68:251 (1980); Ellis, et al., Ann. Rev. Cell Bio. 7:663 (1991)).Apoptotic cells and bodies are usually recognized and cleared byneighboring cells or macrophages before lysis. Because of this clearancemechanism, inflammation is not induced despite the clearance of greatnumbers of cells (Orrenius, S., J. Internal Medicine 237:529–536(1995)).

It has been found that a group of proteases are a key element inapoptosis (see, e.g., Thornberry, Chemistry and Biology 5:R97–R103(1998); Thornberry, British Med. Bull. 53:478–490 (1996)). Geneticstudies in the nematode Caenorhabditis elegans revealed that apoptoticcell death involves at least 14 genes, two of which are thepro-apoptotic (death-promoting) ced (for cell death abnormal) genes,ced-3 and ced-4. CED-3 is homologous to interleukin 1 beta-convertingenzyme, a cysteine protease, which is now called caspase-1. When thesedata were ultimately applied to mammals, and upon further extensiveinvestigation, it was found that the mammalian apoptosis system appearsto involve a cascade of caspases, or a system that behaves like acascade of caspases. At present, the caspase family of cysteineproteases comprises 14 different members, and more may be discovered inthe future. All known caspases are synthesized as zymogens that requirecleavage at an aspartyl residue prior to forming the active enzyme.Thus, caspases are capable of activating other caspases, in the mannerof an amplifying cascade.

Apoptosis and caspases are thought to be crucial in the development ofcancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds.,Humana Press (1999)). There is mounting evidence that cancer cells,while containing caspases, lack parts of the molecular machinery thatactivates the caspase cascade. This makes the cancer cells lose theircapacity to undergo cellular suicide and the cells become cancerous. Inthe case of the apoptosis process, control points are known to existthat represent points for intervention leading to activation. Thesecontrol points include the CED-9-BCL-like and CED-3-ICE-like gene familyproducts, which are intrinsic proteins regulating the decision of a cellto survive or die and executing part of the cell death process itself,respectively (see, Schmitt, et al., Biochem. Cell. Biol. 75:301–314(1997)). BCL-like proteins include BCL-XL and BAX-alpha, which appear tofunction upstream of caspase activation. BCL-xL appears to preventactivation of the apoptotic protease cascade, whereas BAX-alphaaccelerates activation of the apoptotic protease cascade.

It has been shown that chemotherapeutic (anti-cancer) drugs can triggercancer cells to undergo suicide by activating the dormant caspasecascade. This may be a crucial aspect of the mode of action of most, ifnot all, known anticancer drugs (Los, et al., Blood 90:3118–3129 (1997);Friesen, et al., Nat. Med. 2:574 (1996)). The mechanism of action ofcurrent antineoplastic drugs frequently involves an attack at specificphases of the cell cycle. In brief, the cell cycle refers to the stagesthrough which cells normally progress during their lifetimes. Normally,cells exist in a resting phase termed G_(o). During multiplication,cells progress to a stage in which DNA synthesis occurs, termed S.Later, cell division, or mitosis occurs, in a phase called M.Antineoplastic drugs such as cytosine arabinoside, hydroxyurea,6-mercaptopurine, and methotrexate are S phase specific, whereasantineoplastic drugs such as vincristine, vinblastine, and paclitaxelare M phase specific. Many slow growing tumors, for example coloncancers, exist primarily in the G_(o) phase, whereas rapidlyproliferating normal tissues, for example bone marrow, exist primarilyin the S or M phase. Thus, a drug like 6-mercaptopurine can cause bonemarrow toxicity while remaining ineffective for a slow growing tumor.Further aspects of the chemotherapy of neoplastic diseases are known tothose skilled in the art (See, e.g., Hardman, et al., eds., Goodman andGilman's The Pharmacological Basis of Therapeutics, Ninth Edition,McGraw-Hill, New York (1996), pp. 1225–1287). Thus, it is clear that thepossibility exists for the activation of the caspase cascade, althoughthe exact mechanisms for doing so are not clear at this point. It isequally clear that insufficient activity of the caspase cascade andconsequent apoptotic events are implicated in various types of cancer.The development of caspase cascade activators and inducers of apoptosisis a highly desirable goal in the development of therapeuticallyeffective antineoplastic agents. Moreover, since autoimmune disease andcertain degenerative diseases also involve the proliferation of abnormalcells, therapeutic treatment for these diseases could also involve theenhancement of the apoptotic process through the administration ofappropriate caspase cascade activators and inducers of apoptosis.

Eur. Pat. Appl. EP 407899 discloses aminopyrimidine derivatives withactivity as fungicide:

wherein,

-   R₁ is H, alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, alkenyl,    alkynyl, cycloalkyalkyl, substituted aminoalkyl, phenyl,    phenylalkyl, phenoxyalkyl, phenylmercaptoalkyl or    phenoxyphenoxyalkyl, wherein the phenyl-portions are optionally    substituted;-   R₂, R₃, R₄ independently are H, alkyl or optionally substituted    phenyl;-   R₅ is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkoxy,    alkylthio, alkoxyalkyl, R₇R₈N—, alkylthioalkyl, R₇R₈-alkyl, halogen,    alkenyl, alkynyl, phenyl, phenoxy, phenylalkyl, phenoxyalkyl,    phenylmercaptoalkyl, phenylmercapto, phenylalkoxy or    phenylalkylthio, wherein the phenyl-portions are optionally    substituted;-   R₆ is H, alkyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, halogen    or optionally substituted phenyl; or-   R₅ and R₆ are taken together to form a polymethylene group;-   R₇ and R₈ independently are H, alkyl, alkoxyalkyl, hydroxyalkyl,    alkylthioalkyl, alkenyl, substituted aminoalkyl, alkynyl,    cycloalkyl, cycloalkylalkyl, which in the cycloalkyl-portion is    optionally substituted, formyl, phenyl or phenylalkyl, which in the    phenyl-portion is optionally substituted; or-   R₇ and R₈ are taken together with the nitrogen atom to which they    are attached to form an optionally substituted 5- to 7-member,    saturated or unsaturated, heterocycle with 1 or 3 heteroatoms, which    are the same or different; and-   the acid addition salts which are functional as fungicides.

WO 0127089 patent application discloses pyrimidine derivatives for thetreatment of diseases or medical conditions mediated by cytokines:

wherein,

-   m is 0, 1, 2 or 3 are each R¹ group, which may be the same or    different, is selected from hydroxy, halogeno, trifluoromethyl,    cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl,    sulphamoyl, (1–6C)alkyl, (1–6C)alkoxy, (1–6C)alkylthio,    (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,    di[(1–6C)alkyl]amino, (1–6C)alkylsulphonyl, N-(1–6C)alkycarbamoyl,    N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,    (2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,    N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,    (1–6C)alkanesulphonylamino and    N-(1–6C)alkyl-(1–6C)alkanesulphonylamino, or from a group of the    formula:    Q²-X¹—-    wherein X¹ is a direct bond or is selected from O, S, SO, SO₂,    N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴), N(R⁴)SO₂,    OC(R⁴)₂, SC(R⁴)₂ and N(R⁴)C(R⁴)₂, wherein each R⁴ is hydrogen or    (1–6C)alkyl, and Q² is aryl-(1–6C)alkyl, heteroaryl-(1–6C)alkyl,    heterocyclyl or heterocyclyl-(1–6C)alkyl, or (R¹)_(m) is    (1–3C)alkylenedioxy, and wherein any aryl, heteroaryl or    heterocyclyl group within a substituted on R¹ optionally bears 1, 2    or 3 substituents,-   R₃ is hydrogen, halogeno or (1–6C)alkyl;-   n is 0, 1 or 2 and each R² group, which may be the same or different    is selected from hydroxy, halogeno, trifluoromethyl, cyano,    mercapto, nitro, amino, carboxy, (1–6C)alkoxycarbonyl, (1–6C)alkyl,    (1–6C)alkoxy, (1–6C)alkylamino and di[(1–6C)alkyl]amino;-   p is 0, 1, 2, 3, or 4; and-   Q¹ is aryl or heteroaryl and Q¹ is optionally substituted with 1, 2,    or 3 substituents, which may be the same of different, selected from    hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,    carboxy, carbamoyl, formyl, (1–6C)alkyl, (1–6C)alkoxy,    (1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,    (1–6C)alkylamino, di[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,    N-(1–6C)alkycarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl,    (2–6C)alkanoyl, (2–6C)alkanoyloxy, (2–6C)alkanoylamino,    N-(2–6C)alkyl-(2–6C)alkanoylamino, N-(2–6C)alkylsulphamoyl,    N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino and    N-(1–6C)alkyl-(1–6C)alkanesulphonylamino, or with a    (1–3C)alkylenedioxy group, or from a group of the formula:    —X³-Q⁴-    wherein X³ is a direct a bond or is selected from O and N(R⁸),    Wherein R⁸ is hydrogen or (1–6C)alkyl, and Q⁴ is aryl,    aryl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)-alkyl, heterocyclyl    or heterocyclyl(1–6C)alkyl, and any Q⁴ group optionally bears 1 or 2    substituents, which may be the same of different, selected from    halogeno, trifluoromethyl, cyano, hydroxy, amino, (1–6C)alkyl,    (1–6C)alkoxy, (1–6C)alkylamino and di-[(1–6C)alkyl]amino.

WO 0027824 patent application discloses substituted pyrimidinecompositions and methods of use. The compounds are said to have activityas inhibitors of phospholipase A₂, and are useful in treating disordersmediated by phospholipase A₂:

wherein,

-   the symbol R₁ represents a C₁–C₆ alkyl, C₁–C₆ alkoxy or halogen    atom. The symbol R₂ represents a phenyl group, substituted phenyl    group, benzyl moiety, substituted benzyl moiety, C₃–C₇ cycloalkyl,    or substituted C₃–C₇ cycloalkyl. The symbol R₃ represents a hydrogen    or C₁–C₆ alkyl group. The symbol R₄ represents —H, —OH, —N₃ or    —NHCOCH₃. The symbol R₅ represents H or alkyl, preferably H.

U.S. Pat. No. 6,156,755 discloses the use of pyridine derivatives forthe prevention of cancer:

wherein,

-   R¹ is hydrogen, halogen, cyano, nitro, trifluoromethyl, amino,    (C₁–C₆)-alkyl, (C₁–C₆)-hydroxyalkyl, (C₁–C₆)-alkoxy, (C₆–C₁₂)-aryl,    (C₁–C₆)-alkoxycarbonyl-(C₁–C₆)-alkyl, (C₁–C₆)-alkyl-S—(C₁–C₆)-alkyl,    (C₁–C₆)-alkyl-SO—(C₁–C₆)-alkyl, (C₁–C₆)-alkyl-SO₂—(C₁–C₆)-alkyl,    dihydroxy-(C₁–C₆)-alkyl, aryl, heteroaryl, heteroaryl-(C₁–C₆)-alkyl,    aryl-(C₁–C₆)-alkyl, (C₁–C₆)-alkoxycarbonylaryl,    aryl-(C₁–C₆)-alkyloxy or heteroaryl-(C₁–C₆)-alkyloxy, heteroaryl is    pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl,    triazolyl, thiazolyl, oxazolyl, benzothiazolyl;-   R², R³ independently of one another are hydrogen, (C₁–C₆)-alkyl,    (C₆–C₁₂)aryl, (C₆–C₁₂)-arylalkyl having 1–4 alkyl carbon atoms,    where aryl can be substituted by one to three substituents selected    from the group consisting of chlorine, bromine, trifluoromethyl,    (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy, or-   R², R³, together with the nitrogen to which they are bonded, form    the azetidino, pyrrolidino, piperidino, piperazino or morpholino    group, where the heterocycles can be substituted by one or two    substituents selected from the group consisting of chlorine,    bromine, trifluoromethyl, (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy,    —S—(C₁–C₆)-alkyl, —SO—(C₁–C₆)-alkyl, —SO₂—(C₁–C₆)-alkyl, sulfamoyl,    N—(C₁–C₄)-alkylsulfamoyl, N,N—(C₁–C₄)-dialkylsulfamoyl,    (C₁–C₆)-alkoxycarbonyl, N,N—(C₁–C₄)-dialkylcarbamoyl,    N—(C₁–C₄)-alkylcarbamoyl, N—(C₆–C₁₂)-arylcarbamoyl,    (C₆–C₁₂)-arylcarbamoyl substituted in the aryl radical by    (C₁–C₄)-alkyl, (C₁–C₄)-alkoxyl, halogen, NO₂, NH₂, CN or CF₃,    (C₆–C₁₂)-arylcarbonyl substituted in the aryl radical by    (C₁–C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, (C₁–C₆)-alkylsulfonyl,    (C₁–C₆)-alkylsulfinyl, (C₆–C₁₂)-arylsulfonyl, (C₆–C₁₂)-arylsulfonyl    substituted in the aryl radical by (C₁–C₄)-alkyl, (C₁–C₄)-alkoxy,    halogen, NO₂, NH₂, CN or CF₃, heteroarylcarbonyl or    heteroarylsulfonyl;-   R⁴ and R⁵ independently of one another are hydrogen, halogen, cyano,    nitro, trifluoromethyl, amino, (C₁–C₆)-alkyl, (C₁–C₆)-hydroxyalkyl,    (C₁–C₆)-alkoxy, (C₆–C₁₂)-aryl, naphthyl, furyl, where (C₆–C₁₂)-aryl,    naphthyl and furyl can be substituted by one or two substituents    selected from the group consisting of chlorine, bromine,    trifluoromethyl, (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy, —S—(C₁–C₆)-alkyl,    —SO—(C₁–C₆)-alkyl, —SO₂—(C₁–C₆)-alkyl, hydroxyl; and their    physiologically tolerable salts.

SUMMARY OF THE INVENTION

The present invention is related to the discovery that substituted2-aryl-4-arylaminopyrimidines and analogs, as represented in Formula I,are activators of the caspase cascade and inducers of apoptosis. Thus,an aspect of the present invention is directed to the use of compoundsof Formula I as inducers of apoptosis.

Compounds of the present invention are represented by Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

-   Ar₁ and Ar₂ are independently and optionally substituted aryl or    heteroaryl;-   A is N or C—R₂;-   R₁ and R₂ are independently hydrogen, halo, haloalkyl, aryl, fused    aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl,    alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,    heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,    carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino,    cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy,    arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and-   R₃ is hydrogen, an optionally substituted alkyl or cycloalkyl.

A second aspect of the present invention is to provide a method fortreating, preventing or ameliorating neoplasia and cancer byadministering a compound of Formula I to a mammal in need of suchtreatment.

Many of the compounds within the scope of the present invention arenovel compounds. Therefore, a third aspect of the present invention isto provide novel compounds of Formula I, and to also provide for the useof these novel compounds for treating, preventing or amelioratingneoplasia and cancer.

A fourth aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the induction ofapoptosis, containing an effective amount of a compound of Formula I inadmixture with one or more pharmaceutically acceptable carriers ordiluents.

A fifth aspect of the present invention is directed to methods for thepreparation of novel compounds of Formula I.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIGS. 1A–B are graphs showing drug induced cell cycle arrest andapoptosis in T47D cells. FIG. 1A: control cells showing most of thecells in G1 phase of the cell cycle (M2). FIG. 1B: cells treated with200 nM of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine for48 h showing a reduction in the G1 population (M2), an increase in theG2/M population (M4) and the sub-diploid DNA population of cells (M1).

FIG. 2 is a graph showing inhibition of clonogenic survival of MX-1 andT47D cells treated for 48 h with different concentrations of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine. FIG.2 shows increasing inhibition of clonogenicity with increasing drugconcentration, with IC50 of about 100 nM and 300 nM for T47D and MX-1cells, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention arises out of the discovery that substituted2-aryl-4-arylaminopyrimidines and analogs, as represented in Formula I,are potent and highly efficacious activators of the caspase cascade andinducers of apoptosis. Therefore compounds of Formula I are useful fortreating disorders responsive to induction of apoptosis.

Specifically, compounds of the present invention are represented byFormula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

-   Ar₁ and Ar₂ are independently and optionally substituted aryl or    heteroaryl;-   A is N or C—R₂;-   R₁ and R₂ are independently hydrogen, halo, haloalkyl, aryl, fused    aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl,    alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,    heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,    carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino,    cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy,    arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and-   R₃ is hydrogen, an optionally substituted alkyl or cycloalkyl.

Preferred compounds of Formula I include compounds wherein Ar₁ or Ar₂ isoptionally substituted phenyl, naphthyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, quinolyl, isoquinolyl, thienyl, furyl, or pyrrolyl.Preferred compounds of Formula I also include compounds wherein R₃ ishydrogen. Preferred compounds of Formula I also include compoundswherein A is C—R₂. Especially preferred compounds of Formula I includecompounds wherein Ar₁ is optionally substituted pyridinyl, pyrimidinyland pyrazinyl. Especially preferred compounds of Formula I also includecompounds wherein Ar₂ is optionally substituted phenyl, pyridinyl,pyrimidinyl, pyrazinyl and indolyl.

Preferred structures of Formula I are substituted2-aryl-4-arylaminopyrimidines and analogs represented by Formula II:

or pharmaceutically acceptable salts or prodrugs thereof, wherein R₁–R₃,and Ar₂ are as defined in Formula I;

-   B is N or C—R₄;-   D is N or C—R₅;-   E is N or C—R₆;-   F is N or C—R₇;-   G is N or C—R₈; and-   R₄–R₈ are independently hydrogen, halo, haloalkyl, aryl, fused aryl,    carbocyclic, a heterocyclic group, a heteroaryl group, alkyl,    alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,    heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,    carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino,    cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy,    arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol;    provided that not more than three of B, D, E, F and G are N.

Preferred compounds falling within the scope of Formula II includecompounds wherein R₁ is an optionally substituted alkyl, haloalkyl orphenyl. Preferred compounds of Formula II also include compounds whereinAr₂ is an optionally substituted phenyl, pyridinyl, pyrimidinyl,pyrazinyl and indolyl. Preferred compounds of Formula II also includecompounds wherein B is nitrogen, D is C—R₅, E is C—R₆, F is C—R₇, and Gis C—R₉. Preferred compounds of Formula II also include compoundswherein D is nitrogen, B is C—R₄, E is C—R₆, F is C—R₇, and G is C—R₉.Preferred compounds of Formula II also include compounds wherein E isnitrogen, D is C—R₅, B is C—R₄, F is C—R₇, and G is C—R₈. Preferredcompounds of Formula II also include compounds wherein two of B, D, E, Fand G are N.

Preferred structures of Formula I are substituted2-aryl-4-arylaminopyrimidines and analogs represented by Formula III:

or pharmaceutically acceptable salts or prodrugs thereof, wherein R₁–R₃,and B, D, E, F and G are as defined in Formula I and II;

-   R₉–R₁₃ are independently hydrogen, halo, haloalkyl, aryl, fused    aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl,    alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,    heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,    carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino,    cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy,    arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol.

Preferred compounds falling within the scope of Formula III includecompounds wherein R₁ is an optionally substituted alkyl, haloalkyl.Preferred compounds of Formula III also include compounds wherein R₂ ishydrogen. Preferred compounds of Formula III also include compoundswherein one of the B, D, E, F and G is nitrogen. Preferred compounds ofFormula III also include compounds wherein two of the B, D, E, F and Gis nitrogen. Preferred compounds of Formula III also include compoundswherein R₁₀ or R₁₂ are not hydrogen. Preferred compounds of Formula IIIalso include compounds wherein R₉ and R₁₂ are not hydrogen. Preferredcompounds of Formula III also include compounds wherein R₁₀ and R₁₂ arenot hydrogen. Preferred compounds of Formula III also include compoundswherein R₉, R₁₁ and R₁₂ are not hydrogen.

Exemplary preferred compounds that may be employed in the method of theinvention include, without limitation:

4-(3-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Fluoroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dichloroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,4-Difluoroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methylanilino)-2-phenyl-6-methylpyrimidine;

4-(4-Methoxyanilino)-2-(2-hydroxyphenyl)-6-methylpyrimidine;

4-(4-(Trifluoromethoxy)anilino)-2-(pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-(Trifluoromethyl)anilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-(Trifluoromethyl)anilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,4-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Chloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Fluoroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Fluoroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-(Trifluoromethyl)anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Chloroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloroanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;

4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;

4-(3-Chloroanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;

4-(4-(Trifluoromethoxy)anilino)-2-(2-pyridinyl)-6-t-butylpyrimidine;

4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-t-butylpyrimidine;

4-(3-Methoxyanilino)-2-phenyl-6-chloropyrimidine;

4-(4-Methoxyanilino)-2-phenyl-6-chloropyrimidine;

4-(3-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(4-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Fluoroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3,4,5-Trimethoxyanilino)-2-(N-pyrrolyl)-1,3,5-triazine;

4-(3,5-Dichloroanilino)-2-(N-pyrrolyl)-1,3,5-triazine;

4-[2-(Trifluoromethyl)benzylamino]-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Methoxyanilino)-2-(3-methylphenyl)-6-(methoxymethyl)pyrimidine;

4-(2-Chloroanilino)-2-(N-pyrrolyl)-1,3,5-triazine;

4-(2,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Dimethylaminoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Isopropylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-(3-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;

4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3,4-Methylenedioxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

4-[2-Methyl-5-(carboxymethylester)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Fluoro-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methyl-5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Ethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Ethylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methylmercaptoanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Hydroxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;

4-(3,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;

4-(2,5-Diethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Carboxyl-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Chloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,6-Dimethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2-Methoxy-5-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Methoxy-5-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Cyano-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Chloro-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine;

4-(5-Bromo-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Bromo-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-Methyl-5-(trifluoromethyl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Chloro-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,4-Dichloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(Indol-4-ylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Acetyl-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methyl-5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

N-[4-Methyl-3-(2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-Methyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;

6-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;

N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]-4-morpholino-benzamide;

4-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-Methoxy-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-Chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,5-Dimethyl-4-hydroxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4-Chloro-2,5-dimethoxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Trifluoromethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

4-(4-Chloro-2,5-dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Hydroxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(4-pyridinyl)-6-trifluoromethylpyrimidine;

4-(Indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;

6-Methyl-4-(3-phenoxyanilino)-2-(2-pyridinyl)pyrimidine;

4-(3-Chloroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(4-Fluoro-3-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Isopropoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-6-trifluoromethyl-2-(2-pyridinyl)pyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-5-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Methoxy-2-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Carboxy-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluormethylpyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Hydroxy-5-isopropylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2,5-Dimethylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-isopropylanilino)-2-(2-pyrazinyl)-6-trifluoromethypyrimidine;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Cyano-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2,6-Dimethoxypyridin-3-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-pyridin-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(4,6-Dimethoxy-pyrimidin-2-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Hydroxy-5-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(Indol-4-ylamino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methyl-indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-methoxy-anilino)-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidinehydrochloride;

4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(t-butyl)pyrimidine;

4-(3-Methoxyanilino)-2-(2-piperidinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl-N-oxide)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2-methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,4,5-Trimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;and

4-(2,4-Dichloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine.

The present invention is also directed to novel compounds within thescope of Formulae I–III. Exemplary preferred compounds that may beemployed in this invention include, without limitation:

4-(3-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(4-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Fluoroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(4-Methoxyanilino)-2-(3-methylphenyl)-6-(methoxymethyl)pyrimidine;

4-(3-Benzyloxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Ethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Cyanoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Acetophenonanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methoxyanilino)-2-(3-methylphenyl)-6-(methoxymethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-[3-(Trifluoromethyl)anilino]-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Acetoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Nitroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-[3-(Trifluoromethoxy)anilino]-6-methyl-2-(2-pyridinyl)pyrimidine;

4-[3-(Methylthio)anilino]-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Dimethylaminoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Isopropylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-(3-Methoxy-phenoxy)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-5-methoxy-2-(2-pyridinyl)pyrimidine;

4-(3-Methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;

4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;

6-Morpholino-4-(3-methoxyanilino)-2-phenyl-pyrimidine;

6-Morpholino-4-(2,5-dimethoxyanilino)-2-phenyl-4-pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;

4-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(2-Methyl-pyrimidin-4-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Phenylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(3-Nitrophenyl)anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(2,3,4,5,6-Pentafluorophenoxy)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(2-Ethyl-1-phenyl-pyrazolin-5-one-3-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(Phenylsulfone)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-(N-phenylamide)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3,4-Methylenedioxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;

4-(3,4-Methylenedioxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

4-[2-Methyl-5-(carboxymethylester)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Fluoro-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methyl-5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Ethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Ethylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methylmercaptoanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Hydroxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;

4-(3,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;

4-(2,5-Diethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Carboxyl-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(3-Methoxybenzylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Carboxyl-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,6-Dimethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(5-Methoxy-2-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2-Methoxy-5-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethylanilino)-2,6-di(2-pyridinyl)pyrimidine;

4-(2,5-Dimethylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Methoxy-5-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Methoxy-2-piperidino-anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Cyano-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Chloro-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(3-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine;

4-(5-Bromo-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Bromo-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-[3-Methyl-5-(trifluoromethyl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Chloro-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Chloro-5-methoxyanilino)-2-morpholino-6-(methyl)pyrimidine;

4-(2,4-Dichloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(Indol-4-ylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Acetyl-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Methyl-5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(5-Amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

N-[4-Methyl-3-(2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-(2,5-Diethoxy-4-morpholinoanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-Methyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;

6-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;

N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]-4-morpholino-benzamide;

4-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-Methoxy-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-Chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,5-Dimethyl-4-hydroxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4-Chloro-2,5-dimethoxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Chloro-5-methoxyanilino)-6-methyl-2-aminopyrimidine;

4-(3-Trifluoromethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(4,5-Dimethoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

4-(4-Chloro-2,5-dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;

4-(2-Hydroxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(N-Methyl-3-methoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(4-pyridinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(2-Methoxy-5-methyl-4-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(Indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(5-Methoxy-2-methyl-4-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(3-Trifluoromethyl-1-pyrazolyl)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(4,5-Dihydro-2-thiazolyl-amino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(1-Pyrazolyl)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;

4-(4,5,6,7-Tetrahydro-indazol-1-yl)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(1H-3-Pyrazolyl-amino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

6-Methyl-2-(2-pyridinyl)-4-(3-trifloromethylbenzylamino)-pyrimidine;

6-Methyl-4-(3-phenoxyanilino)-2-(2-pyridinyl)pyrimidine;

4-(3-Chloroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(4-Fluoro-3-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3-Isopropoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;

4-(3,4-Dimethoxyanilino)-6-trifluoromethyl-2-(2-pyridinyl)pyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-5-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Methoxy-2-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Carboxy-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Ethanesulfonyl-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluormethylpyrimidine;

4-(2-Methoxy-5-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Ethanesulfonyl-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Hydroxy-5-isopropylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(3,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2,5-Dimethylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;

4-(5-Hydroxy-2-isopropylanilino)-2-(2-pyrazinyl)-6-trifluoromethypyrimidine;

4-(2,5-Dimethoxyphenylethylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2,5-Dimethyl-4-hydroxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(3,4,5-Trichloroanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Cyano-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(3-Methoxy-dibenzofuran-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(1,5,6-Trimethyl-benzimidazol-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2,6-Dimethoxypyridin-3-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methoxy-pyridin-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(4,6-Dimethoxy-pyrimidin-2-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(5-Chloro-2-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Hydroxy-5-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(1,3,4-Triazol-1-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(Indol-4-ylamino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Methyl-indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;

4-(2-Chloro-5-methoxy-anilino)-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidinehydrochloride;

4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(t-butyl)pyrimidine;

4-(3-Methoxyanilino)-2-(2-piperidinyl)-6-(trifluoromethyl)pyrimidine;

4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl-N-oxide)-6-(trifluoromethyl)pyrimidine;

4-(4-Chloro-2-methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;

4-(2,4,5-Trimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;and

4-(2,4-Dichloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,3-pentyl, hexyl and octyl groups, which may be optionally substituted.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted.

Useful alkylthio groups include sulphur substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted. Alsoincluded are the sulfoxides and sulfones of such alkylthio groups.

Useful amino groups include —NH₂, —NHR₁₅ and —NR₁₅R₁₆, wherein R₁₅ andR₁₆ are C₁₋₁₀ alkyl or cycloalkyl groups, or R₁₅ and R₁₆ are combinedwith the N to form a ring structure, such as a piperidine, or R₁₅ andR₁₆ are combined with the N and other group to form a ring, such as apiperazine. The alkyl group may be optionally substituted.

Optional substituents on the alkyl and cycloalkyl groups include one ormore halo, hydroxy, carboxyl, amino, nitro, cyano, C₁–C₆ acylamino,C₁–C₆ acyloxy, C₁–C₆ alkoxy, aryloxy, alkylthio, C₆–C₁₀ aryl, C₄–C₇cycloalkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₆–C₁₀ aryl(C₂–C₆)alkenyl,C₆–C₁₀ aryl(C₂–C₆)alkynyl, saturated and unsaturated heterocyclic orheteroaryl.

Optional substituents on the aryl, arylalkyl and heteroaryl groupsinclude one or more halo, C₁–C₆ haloalkyl, C₆–C₁₀ aryl, C₄–C₇cycloalkyl, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₆–C₁₀aryl(C₁–C₆)alkyl, C₆–C₁₀ aryl(C₂–C₆)alkenyl, C₆–C₁₀ aryl(C₂–C₆)alkynyl,C₁–C₆ hydroxyalkyl, nitro, amino, ureido, cyano, C₁–C₆ acylamino,hydroxy, thiol, C₁–C₆ acyloxy, azido, C₁–C₆ alkoxy or carboxy.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic, bicyclic or tricyclic aromatic groups containingfrom 6 to 14 carbons in the ring portion.

Useful aryl groups include C₆₋₁₄ aryl, preferably C₆₋₁₀ aryl. TypicalC₆₋₁₄ aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl,indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups are C₃₋₈ cycloalkyl. Typical cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Useful saturated or partially saturated carbocyclic groups arecycloalkyl groups as described above, as well as cycloalkenyl groups,such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.Preferably the arylalkyl group is benzyl, phenylethyl or naphthylmethyl.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl,chloromethyl, chlorofluoromethyl and trichloromethyl groups.

Useful acylamino(acylamido) groups are any C₁₋₆ acyl(alkanoyl) attachedto an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido,butanoylamido, pentanoylamido and hexanoylamido, as well asaryl-substituted C₁₋₆ acylamino groups, e.g., benzoylamido, andpentafluorobenzoylamido.

Useful acyloxy groups are any C₁₋₆ acyl(alkanoyl) attached to an oxy(—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy,pentanoyloxy and hexanoyloxy.

The term heterocycle is used herein to mean a saturated or partiallysaturated 3–7 membered monocyclic, or 7–10 membered bicyclic ringsystem, which consists of carbon atoms and from one to four heteroatomsindependently selected from the group consisting of O, N, and S, whereinthe nitrogen and sulfur heteroatoms can be optionally oxidized, thenitrogen can be optionally quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, and wherein the heterocyclic ring can be substituted oncarbon or on a nitrogen atom if the resulting compound is stable.

Useful saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl,tetronoyl and tetramoyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms.

Useful heteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl,isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl,cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl,acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl,1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin,pyrido[1,2-a]pyrimidin-4-one, 1,2-benzoisoxazol-3-yl, benzimidazolyl,2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group containsa nitrogen atom in a ring, such nitrogen atom may be in the form of anN-oxide, e.g., a pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinylN-oxide.

Some of the compounds of the present invention may exist asstereoisomers including optical isomers. The invention includes allstereoisomers and both the racemic mixtures of such stereoisomers aswell as the individual enantiomers that may be separated according tomethods that are well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate and oxalate; and inorganic and organic base addition saltswith bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane(TRIS, tromethane) and N-methyl-glucamine.

Examples of prodrugs of the compounds of the invention include thesimple esters of carboxylic acid containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ alcohol according to methods knownin the art); esters of hydroxy containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ carboxylic acid, C₃₋₆ dioic acid oranhydride thereof such as succinic and fumaric anhydrides according tomethods known in the art); phosphate of hydroxy containing compounds(e.g. combretastatin A-1 phosphate prodrug, see Pettit G. R. and LippertIII, J. W., Anticancer Drug Design 15:203–216 (2000)); imines of aminocontaining compounds (e.g., those obtained by condensation with a C₁₋₄aldehyde or ketone according to methods known in the art); carbamate ofamino containing compounds such as those described by Leu, et. al., (J.Med. Chem. 42:3623–3628 (1999)) and Greenwald, et. al., (J. Med. Chem.42:3657–3667 (1999)); and acetals and ketals of alcohol containingcompounds (e.g., those obtained by condensation with chloromethyl methylether or chloromethyl ethyl ether according to methods known in theart).

The compounds of this invention may be prepared using methods known tothose skilled in the art, or the novel methods of this invention.Specifically, the compounds of this invention with Formulae I–III may beprepared as illustrated by the exemplary reaction in Scheme 1. Reactionof 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine with aniline gave theproduct 4-anilino-6-methyl-2-(2-pyridinyl)pyrimidine.

The 2-aryl-4-chloro-pyrimidine may be prepared as illustrated by theexemplary reaction in Scheme 2. Reaction of pyridine-2-carboxamidinewith 4,4,4-trifluoro-but-2-ynoic acid ethyl ester in ethanol in thepresence of base such as KOH produced the substituted4-hydroxy-pyrimidine. Treatment of the hydroxy-pyrimidine with POCl₃gave the product 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine.

Alternatively, the 2-aryl-4-chloro-pyrimidine may be prepared asillustrated by the exemplary reaction in Scheme 3. Reaction ofpyrimidine-2-carboxamidine with ethyl 4,4,4-trifluoro-acetoacetate inethanol in the presence of base such as EtONa produced the substituted4-hydroxy-pyrimidine. Treatment of the hydroxy-pyrimidine with POCl₃gave the product 4-chloro-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidine.

An important aspect of the present invention is the discovery thatcompounds having Formula I–III are activators of caspases and inducersof apoptosis. Therefore, these compounds are useful in a variety ofclinical conditions in which there is uncontrolled cell growth andspread of abnormal cells, such as in the case of cancer.

Another important aspect of the present invention is the discovery thatcompounds having Formula I–III are potent and highly efficaciousactivators of caspases and inducers of apoptosis in drug resistantcancer cells, such as breast cancer cells (Examples 11–14), whichenables these compounds to kill these drug resistant cancer cells. Incomparison, most standard anti-cancer drugs are not effective in killingdrug resistant cancer cells under the same conditions. Therefore,compounds of this invention are useful for the treatment of drugresistant cancer such as breast cancer in animals.

The present invention includes a therapeutic method useful to modulatein vivo apoptosis or in vivo neoplastic disease, comprisingadministering to a subject in need of such treatment an effective amountof a compound, or a pharmaceutically acceptable salt or prodrug of thecompound of Formulae I–III, which functions as a caspase cascadeactivator and inducer of apoptosis.

The present invention also includes a therapeutic method comprisingadministering to an animal an effective amount of a compound, or apharmaceutically acceptable salt or prodrug of said compound of FormulaeI–III, wherein said therapeutic method is useful to treat cancer, whichis a group of diseases characterized by the uncontrolled growth andspread of abnormal cells. Such diseases include, but are not limited to,Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphatic leukemia,chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breastcarcinomas, ovarian carcinomas, lung carcinomas, Wilms' tumor, cervicalcarcinomas, testicular carcinomas, soft-tissue sarcomas, primarymacroglobulinemia, bladder carcinomas, chronic granulocytic leukemia,primary brain carcinomas, malignant melanoma, small-cell lungcarcinomas, stomach carcinomas, colon carcinomas, malignant pancreaticinsulinoma, malignant carcinoid carcinomas, malignant melanomas,choriocarcinomas, mycosis fungoides, head or neck carcinomas, osteogenicsarcoma, pancreatic carcinomas, acute granulocytic leukemia, hairy cellleukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma,genitourinary carcinomas, thyroid carcinomas, esophageal carcinomas,malignant hypercalcemia, cervical hyperplasia, renal cell carcinomas,endometrial carcinomas, polycythemia vera, essential thrombocytosis,adrenal cortex carcinomas, skin cancer, and prostatic carcinomas.

In practicing the therapeutic methods, effective amounts of compositionscontaining therapeutically effective concentrations of the compoundsformulated for oral, intravenous, local and topical application, for thetreatment of neoplastic diseases and other diseases in which caspasecascade mediated physiological responses are implicated, areadministered to an individual exhibiting the symptoms of one or more ofthese disorders. The amounts are effective to ameliorate or eliminateone or more symptoms of the disorders. An effective amount of a compoundfor treating a particular disease is an amount that is sufficient toameliorate, or in some manner reduce, the symptoms associated with thedisease. Such amount may be administered as a single dosage or may beadministered according to a regimen, whereby it is effective. The amountmay cure the disease but, typically, is administered in order toameliorate the symptoms of the disease. Typically, repeatedadministration is required to achieve the desired amelioration ofsymptoms

In another embodiment, a pharmaceutical composition comprising acompound, or a pharmaceutically acceptable salt of said compound ofFormulae I–III, which functions as a caspase cascade activator andinducer of apoptosis in combination with a pharmaceutically acceptablevehicle is provided.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of said compound of FormulaeI–III, which functions as a caspase cascade activator and inducer ofapoptosis, in combination with at least one known cancerchemotherapeutic agent, or a pharmaceutically acceptable salt of saidagent. Examples of known cancer chemotherapeutic agents which may beused for combination therapy include, but not are limited to alkylatingagents such as busulfan, cis-platin, mitomycin C, and carboplatin;antimitotic agents such as coichicine, vinblastine, paclitaxel, anddocetaxel; topo I inhibitors such as camptothecin and topotecan; topo IIinhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolitessuch as 5-azacytidine, 5-fluorouracil and methotrexate; DNAantimetabolites such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyureaand thioguanine; antibodies such as Herceptin® and Rituxan®. Other knowncancer chemotherapeutic agents which may be used for combination therapyinclude melphalan, chlorambucil, cyclophosphamide, ifosfamide,vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin,mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid,tamoxifen and alanosine.

In practicing the methods of the present invention, the compound of theinvention may be administered together with at least one knownchemotherapeutic agent as part of a unitary pharmaceutical composition.Alternatively, the compound of the invention may be administered apartfrom at least one known cancer chemotherapeutic agent. In oneembodiment, the compound of the invention and at least one known cancerchemotherapeutic agent are administered substantially simultaneously,i.e. the compounds are administered at the same time or one after theother, so long as the compounds reach therapeutic levels in vivo at thesame time. On another embodiment, the compound of the invention and atleast one known cancer chemotherapeutic agent are administered accordingto their individual dose schedule, so long as the compounds reachtherapeutic levels in vivo.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a bioconjugates of saidcompound of Formulae I–III, which functions as a caspase cascadeactivator and inducer of apoptosis, in bioconjugation with at least oneknown therapeutically useful antibody, such as Herceptin® or Rituxan®,growth factors such as EGF, NGF, cytokines such as IL-2, IL-4, or anymolecule that binds to the cell surface. The antibodies and othermolecules will deliver the compound of Formulae I–III to its targets andmake it an effective anticancer agent. The bioconjugates could alsoenhance the anticancer effect of therapeutically useful antibodies, suchas Herceptin® or Rituxan®.

Similarly, another embodiment of the present invention is directed to acomposition effective in inhibiting neoplasia comprising a compound, ora pharmaceutically acceptable salt or prodrug of said compound ofFormulae I–III, which functions as a caspase cascade activator andinducer of apoptosis, in combination with radiation therapy. In thisembodiment, the compound of the invention may be administered at thesame time as the radiation therapy is administered or at a differenttime.

Yet another embodiment of the present invention is directed to acomposition effective for post-surgical treatment of cancer, comprisinga compound, or a pharmaceutically acceptable salt or prodrug of saidcompound of Formulae I–III, which functions as a caspase cascadeactivator and inducer of apoptosis. The invention also relates to amethod of treating cancer by surgically removing the cancer and thentreating the animal with one of the pharmaceutical compositionsdescribed herein.

A wide range of immune mechanisms operate rapidly following exposure toan infectious agent. Depending on the type of infection, rapid clonalexpansion of the T and B lymphocytes occurs to combat the infection. Theelimination of the effector cells following an infection is one of themajor mechanisms for maintaining immune homeostasis. The elimination ofthe effector cells has been shown to be regulated by apoptosis.Autoimmune diseases have lately been determined to occur as aconsequence of deregulated cell death. In certain autoimmune diseases,the immune system directs its powerful cytotoxic effector mechanismsagainst specialized cells such as oligodendrocytes in multiplesclerosis, the beta cells of the pancreas in diabetes mellitus, andthyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K. B., CellDeath Differ. 6:13–21 (1999)). Mutations of the gene encoding thelymphocyte apoptosis receptor Fas/APO-1/CD95 are reported to beassociated with defective lymphocyte apoptosis and autoimmunelymphoproliferative syndrome (ALPS), which is characterized by chronic,histologically benign splenomegaly, generalized lymphadenopathy,hypergammaglobulinemia, and autoantibody formation. (Infante, A. J., etal, J. Pediatr. 133:629–633 (1998) and Vaishnaw, A. K., et al., J. Clin.Invest. 103:355–363 (1999)). It was reported that overexpression ofBcl-2, which is a member of the bcl-2 gene family of programmed celldeath regulators with anti-apoptotic activity, in developing B cells oftransgenic mice, in the presence of T cell dependent costimulatorysignals, results in the generation of a modified B cell repertoire andin the production of pathogenic autoantibodies (Lopez-Hoyos, M., et al.,Int. J. Mol. Med. 1:475–483 (1998)). It is therefore evident that manytypes of autoimmune disease are caused by defects of the apoptoticprocess. One treatment strategy for such diseases is to turn onapoptosis in the lymphocytes that are causing the autoimmune disease(O'Reilly, L. A. & Strasser, A., Inflamm. Res. 48:5–21 (1999)).

Fas-Fas ligand (FasL) interaction is known to be required for themaintenance of immune homeostasis. Experimental autoimmune thyroiditis(EAT), characterized by autoreactive T and B cell responses and a markedlymphocytic infiltration of the thyroid, is a good model to study thetherapeutic effects of FasL. Batteux, F., et al., (J. Immunol.162:603–608 (1999)) reported that by direct injection of DNA expressionvectors encoding FasL into the inflamed thyroid, the development oflymphocytic infiltration of the thyroid was inhibited and induction ofinfiltrating T cells death was observed. These results show that FasLexpression on thyrocytes may have a curative effect on ongoing EAT byinducing death of pathogenic autoreactive infiltrating T lymphocytes.

Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosisin human astrocytoma 1321N1 cells and in Molt-4T cells; both of whichwere resistant to apoptosis induced by anti-Fas antibody in the absenceof bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis bybisindolylmaleimide VIII was reported to be selective for activated,rather than non-activated, T cells, and was Fas-dependent. Zhou T., etal., (Nat. Med. 5:42–48 (1999)) reported that administration ofbisindolylmaleimide VIII to rats during autoantigen stimulationprevented the development of symptoms of T cell-mediated autoimmunediseases in two models, the Lewis rat model of experimental allergicencephalitis and the Lewis adjuvant arthritis model. Therefore, theapplication of a Fas-dependent apoptosis enhancer such asbisindolylmaleimide VIII may be therapeutically useful for the moreeffective elimination of detrimental cells and inhibition of Tcell-mediated autoimmune diseases. Therefore an effective amount of acompound, or a pharmaceutically acceptable salt or prodrug of thecompound of Formulae I–III, which functions as a caspase cascadeactivator and inducer of apoptosis, should be an effective treatment forautoimmune diseases.

Psoriasis is a chronic skin disease that is characterized by scaly redpatches. Psoralen plus ultraviolet A (PVA) is a widely used andeffective treatment for psoriasis vulgaris and Coven, et al.,Photodermatol. Photoimmunol. Photomed. 15:22–27 (1999), reported thatlymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNAdegradation patterns typical of apoptotic cell death. Ozawa, et al., J.Exp. Med. 189:711–718 (1999) reported that induction of T cell apoptosiscould be the main mechanism by which 312-nm UVB resolves psoriasis skinlesions. Low doses of methotrexate may be used to treat psoriasis torestore a clinically normal skin. Heenen, et al., Arch. Dermatol. Res.290:240–245 (1998), reported that low doses of methotrexate may induceapoptosis and that this mode of action could explain the reduction inepidermal hyperplasia during treatment of psoriasis with methotrexate.Therefore, an effective amount of a compound, or a pharmaceuticallyacceptable salt or prodrug of the compound of Formulae I–III, whichfunctions as a caspase cascade activator and inducer of apoptosis,should be an effective treatment for psoriasis.

Synovial cell hyperplasia is a characteristic of patients withrheumatoid arthritis (RA). It is believed that excessive proliferationof RA synovial cells, as well as defects in synovial cell death, may beresponsible for synovial cell hyperplasia. Wakisaka, et al., Clin. Exp.Immunol. 114:119–128 (1998), found that although RA synovial cells coulddie via apoptosis through a Fas/FasL pathway, apoptosis of synovialcells was inhibited by proinflammatory cytokines present within thesynovium. Wakisaka, et al., also suggested that inhibition of apoptosisby the proinflammatory cytokines may contribute to the outgrowth ofsynovial cells, and lead to pannus formation and the destruction ofjoints in patients with RA. Therefore, an effective amount of acompound, or a pharmaceutically acceptable salt or prodrug of thecompound of Formulae I–III, which functions as a caspase cascadeactivator and inducer of apoptosis, should be an effective treatment forrheumatoid arthritis.

There has been an accumulation of convincing evidence that apoptosisplays a major role in promoting resolution of the acute inflammatoryresponse. Neutrophils are constitutively programmed to undergoapoptosis, thus limiting their pro-inflammatory potential and leading torapid, specific, and non-phlogistic recognition by macrophages andsemi-professional phagocytes (Savill, J., J. Leukoc. Biol. 61:375–380(1997)). Boirivant, et al., Gastroenterology 116:557–565 (1999),reported that lamina propria T cells, isolated from areas ofinflammation in Crohn's disease, ulcerative colitis, and otherinflammatory states, manifest decreased CD2 pathway-induced apoptosis.In addition, studies of cells from inflamed Crohn's disease tissueindicate that this defect is accompanied by elevated Bcl-2 levels.Therefore, an effective amount of a compound, or a pharmaceuticallyacceptable salt or prodrug of the compound of Formulae I–III, whichfunctions as a caspase cascade activator and inducer of apoptosis,should be an effective treatment for inflammation.

Pharmaceutical compositions within the scope of this invention includeall compositions wherein the compounds of the present invention arecontained in an amount that is effective to achieve its intendedpurpose. While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.Typically, the compounds may be administered to animals, e.g., mammals,orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or anequivalent amount of the pharmaceutically acceptable salt thereof, to amammal being treated for apoptosis-mediated disorders. Preferably, about0.01 to about 10 mg/kg of body weight is orally administered to treat orprevent such disorders. For intramuscular injection, the dose isgenerally about one-half of the oral dose. For example, a suitableintramuscular dose would be about 0.0025 to about 25 mg/kg of bodyweight, and most preferably, from about 0.01 to about 5 mg/kg of bodyweight. If a known cancer chemotherapeutic agent is also administered,it is administered in an amount that is effective to achieve itsintended purpose. The amounts of such known cancer chemotherapeuticagents effective for cancer are well known to those of skill in the art.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound of the invention.The unit dose may be administered one or more times daily as one or moretablets each containing from about 0.1 to about 10, conveniently about0.25 to 50 mg of the compound or its solvates.

In a topical formulation, the compound may be present at a concentrationof about 0.01 to 100 mg per gram of carrier.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which may beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which may be administered orally and which may be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which may be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular apoptosis inducers of the present invention with asolution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalicacid, and the like. Basic salts are formed by mixing a solution of theparticular apoptosis inducers of the present invention with a solutionof a pharmaceutically acceptable non-toxic base such as sodiumhydroxide, potassium hydroxide, choline hydroxide, sodium carbonate,Tris, N-methyl-glucamine and the like.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humansand veterinary animals, although the invention is not intended to be solimited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, intrathecal,intracranial, intranasal or topical routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usemay be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which may be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules may contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which may be used rectally include,for example, suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400) or cremophor, or cyclodextrins.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension include, for example, sodium carboxymethylcellulose, sorbitol, and/or dextran. Optionally, the suspension may alsocontain stabilizers.

In accordance with one aspect of the present invention, compounds of theinvention are employed in topical and parenteral formulations and areused for the treatment of skin cancer.

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments and the like by choice of appropriatecarriers. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). The preferredcarriers are those in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thesetopical formulations. Examples of such enhancers are found in U.S. Pat.Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture the activeingredient, dissolved in a small amount of an oil such as almond oil, isadmixed. A typical example of such a cream is one which includes about40 parts water, about 20 parts beeswax, about 40 parts mineral oil andabout 1 part almond oil.

Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil such as almond oil with warn soft paraffinand allowing the mixture to cool. A typical example of such an ointmentis one which includes about 30% almond oil and about 70% white softparaffin by weight.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

EXAMPLE 1 4-(4-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

To a mixture of 6-chloro-4-methyl-2-(2-pyridinyl)pyrimidine (15 mg, 0.56mmol), p-anisidine (68 mg, 0.55 mmol) in water (10 mL) was added 2 N HCl(0.3 mL). The mixture was refluxed for 6 h, cooled to room temperature,and neutralized with 2N NaOH to pH 10. The resulting mixture was thenextracted with 1:1 Hexane/EtOAc (50 mL). The organic phase was washedwith water and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by chromatography (1:1 Hexane/EtOAc) to yield theproduct as a tan solid (72 mg, 45%). ¹H NMR (CDCl₃): 8.80 (d, J=4.5 Hz,1H), 8.45 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.4Hz, 2H), 7.12 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 3.83 (s,3H), 2.45 (s, 3H).

EXAMPLE 2 4-(3-Fluoroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (CDCl₃): 8.80 (d, J=4.5 Hz, 1H), 8.46 (d, J=7.5 Hz,1H), 7.84 (m, 1H), 7.56 (s, 1H), 7.39–7.25 (m, 3H), 7.10 (d, J=7.5 Hz,1H), 6.83 (m, 1H), 6.64 (s, 1H), 2.45 (s, 3H).

EXAMPLE 3 4-(3-Methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (CDCl₃): 8.79 (d, J=4.5 Hz, 1H), 8.44 (d, J=7.8 Hz,1H), 7.79 (m, 1H), 7.36–7.09 (m, 5H), 6.98 (d, J=7.5 Hz, 1H), 6.59 (s,1H), 2.46 (s, 3H), 2.35 (s, 3H).

EXAMPLE 4 4-Anilino-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (DMSO-d₆): 9.64 (s, 1H), 8.70 (d, J=4.5 Hz, 1H), 8.28(d, J=7.5 Hz, 1H), 7.94 (m, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.47 (m,1H), 7.31 (m, 1H), 7.02 (m, 1H), 6.66 (s, 1H), 2.38 (s, 3H).

EXAMPLE 5 4-(4-Methoxyanilino)-6-methyl-2-phenylpyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (CDCl₃): 8.39–8.36 (m, 2H), 7.48–7.44 (m, 3H),7.30–7.26 (m, 2H), 6.95–6.93 (m, 2H), 6.68 (s, 1H), 6.32 (s, 1H), 3.84(s, 3H), 2.38 (s, 3H).

EXAMPLE 65-Chloro-4-(4-methoxyanilino)-6-methyl-2-[(5-trifluoromethyl)-2-pyridinyl]pyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (CDCl₃): 9.06 (m, 1H), 8.43 (m, 1H), 8.04 (m, 1H),7.59–7.56 (m, 2H), 7.23 (s, 1H), 7.00–6.97 (m, 2H), 3.87 (s, 3H), 2.71(s, 3H).

EXAMPLE 76-(4-Chlorophenyl)-5-cyano-4-(4-methoxyanilino)-2-pyridinylpyrimidine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (DMSO-d₆): 8.58 (d, J=4.5 Hz, 1H), 8.11 (d, J=7.8 Hz,1H), 7.88–7.77 (m, 3H), 7.54 (d, J=8.7 Hz, 2H), 7.47–7.39 (m, 3H), 6.85(d, J=8.7 Hz, 2H), 3.64 (s, 3H).

EXAMPLE 8 4-(4-Methoxyanilino)-2-phenylquinazoline

To a solution of 4-chloro-2-phenylquinazoline (590 mg, 2.45 mmol) in THF(10 mL) was added m-anisidine (301 mg, 2.45 mmol) and NaH (60%, 120 mg,3.0 mmol). The mixture was refluxed for 24 h. After cooled to roomtemperature, the mixture was diluted with 1:1 hexane/EtOAc (100 mL),washed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by chromatography (3:1 hexane/EtOAc) toyield the title compound as a white solid (173 mg, 0.53 mmol, 22%). ¹HNMR (CDCl₃): 8.54–8.51 (m, 2H), 8.00–7.74 (m, 5H), 7.52–7.47 (m, 4H),7.38 (s, 1H), 7.02–7.00 (m, 2H), 3.88 (s, 3H).

EXAMPLE 9 6-Chloro-4-(4-methoxyanilino)-2-phenylpyrimidine

The title compound was prepared using a similar method as described inExample 8. ¹H NMR (CDCl₃): 8.39–8.36 (m, 1H), 8.48–7.46 (m, 3H),7.28–7.25 (m, 3H), 6.98–6.95 (m, 2H), 6.85 (s, 1H), 6.42 (s, 1H), 3.85(s, 3H).

EXAMPLE 104-(4-Chlorophenyl)-2-(4-methoxyanilino)-6-methylthio-1,3,5-triazine

The title compound was prepared using a similar method as described inExample 1. ¹H NMR (CDCl₃): 8.35 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.7 Hz,2H), 7.42 (d, J=8.7 Hz, 2H), 7.16 (s, 1H), 6.92 (d, J=8.4 Hz, 2H).

EXAMPLE 114-(4-Methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

A mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine(100 mg, 0.402 mmol), p-anisidine (50 mg, 0.402 mmol), water (5 ml) and2N HCl (300 μl) was refluxed overnight. The resulting yellow solid wascollected by filtration, washed with water and then dried under vacuumto give the title compound (55 mg, 41%). ¹H NMR (CDCl₃): 8.28 (d, J=8.7Hz, 2H), 7.43–7.35 (m, 4H), 6.96 (d, J=9.0 Hz, 2H), 6.83 (s, 1H), 4.64(s, 2H), 3.85 (s, 3H), 3.45 (s, 3H), 2.44 (s, 3H).

EXAMPLE 12 4-(4-Methoxyanilino)-6-methyl-2-(3-methylphenyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) andp-anisidine (56 mg, 0.457 mmol), similar to Example 11 as a pale greensolid (39 mg, 28%). ¹H NMR (DMSO-d₆): 8.04 (s, 1H), 8.01–7.99 (m, 1H),7.56–7.51 (m, 4H), 7.04 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.79 (s, 3H),2.44 (s, 6H).

EXAMPLE 134-(4-Dimethylaminoanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

A mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine(100 mg, 0.402 mmol), N,N-dimethyl-1,3-phenylene-diamine dihydrochloride(84 mg, 0.402 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed for 6h. The mixture was diluted with ethyl acetate (50 ml), washed with waterand saturated NaCl. The ethyl acetate solution was dried over anhydroussodium sulfate, concentrated in vacuo and purified by columnchromatography (hexane:ethyl acetate, 3:1) to yield a tan oily product(32 mg, 23%). ¹H NMR (CDCl₃): 8.22–8.20 (m, 1H), 8.18 (s, 1H), 7.34 (t,J=7.5 Hz, 1H), 7.25–7.20 (m, 2H), 6.96 (bs, 1H), 6.89 (s, 1H), 6.82 (s,1H), 6.67 (dd, J=2.0, 8.0 Hz, 1H), 6.53 (dd, J=2.6, 8.6 Hz, 1H), 4.50(m, 2H), 3.47 (m, 3H), 2.97 (s, 6H), 2.42 (s, 3H).

EXAMPLE 144-(4-Dimethylaminoanilino)-6-methyl-2-(3-methylphenyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) andN,N-dimethyl-1,3-phenylene-diamine dihydrochloride (96 mg, 0.457 mmol)similar to Example 13 as a yellow oil (9 mg, 6%). ¹H NMR (CDCl₃): 8.20(s, 1H), 8.17 (s, 1H), 7.34 (t, J=7.5 Hz, 1H), 7.25–7.21 (m, 2H), 6.82(t, J=2.1 Hz, 1H), 6.79 (bs, 1H), 6.66 (dd, J=2.0, 7.7 Hz, 1H), 6.54(dd, J=2.9, 8.9 Hz, 2H), 2.97 (s, 6H), 2.42 (s, 6H).

EXAMPLE 154-(3-Methoxyanilino)-5-chloro-6-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]pyrimidine

The title compound was prepared from4,5-dichloro-6-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]pyrimidine (100mg, 0.325 mmol) and m-anisidine (37 μl, 0.325 mmol) similar to Example11 as a pale white solid (26 mg, 20%). ¹H NMR (CDCl₃): 9.05 (dd, J=0.8,1.4 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.06 (dd, J=2.3, 8.3 Hz, 1H), 7.57(t, J=2.3 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.18–7.14 (m,1H), 6.75–6.72 (m, 1H), 3.88 (s, 3H), 2.71 (s, 3H).

EXAMPLE 16 4-(3-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) andm-anisidine (55 μl, 0.486 mmol) similar to Example 13 as an tan oil (139mg, 98%). ¹HNMR (CDCl₃): 8.78–8.75 (m, 1H), 8.45 (dt, J=1.2, 8.1 Hz,1H), 7.78 (td, J=1.9, 7.8 Hz, 1H), 7.73 (s, 1H), 7.34–7.30 (m, 1H), 7.23(t, J=8.1 Hz, 1H), 7.03 (t, J=2.1 Hz, 1H), 6.92 (dd, J=2.0, 7.7 Hz, 1H),6.67 (dd, J=2.4, 8.1 Hz, 1H), 6.61 (s, 1H), 3.77 (s, 3H), 2.44 (s, 3H).

EXAMPLE 17 4-(3-Methoxyanilino)-6-methyl-2-(3-methylphenyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) andm-anisidine (51 μl, 0.457 mmol) similar to Example 11 as a pale yellowsolid (11 mg, 8%). ¹H NMR (DMSO-d₆): 8.09 (s, 1H), 8.05 (d, J=7.5 Hz,1H), 7.54–7.49 (m, 4H), 7.35 (t, J=8.1 Hz, 1H), 7.21 (s, 1H), 6.78 (s,2H), 3.81 (s, 3H), 2.43 (s, 6H).

EXAMPLE 18 4-(3-Methoxyanilino)-5-methoxy-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (100 mg, 0.451 mmol) andm-anisidine (51 μl, 0.451 mmol) similar to Example 13 and isolated as atan oily liquid (63 mg, 45%). ¹H NMR (CDCl₃): 8.76–8.74 (m, 1H), 8.37(dd, J=1.1, 8.0 Hz, 1H), 8.05 (s, 1H), 7.79–7.73 (m, 2H), 6.65–6.62 (m,1H), 3.92 (s, 3H), 3.84 (s, 3H).

EXAMPLE 194-(3-Methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385mmol) and m-anisidine (43 μl, 0.385 mmol) similar to Example 13 andisolated as a pale yellow solid (38 mg, 29%). ¹H NMR (Acetone-d₆): 9.61(d, J=2.4 Hz, 1H), 9.42 (s, 1H), 8.76–8.70 (m, 2H), 7.57–7.53 (m, 2H),7.39 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.79–6.75 (m, 1H), 3.87 (s,3H).

EXAMPLE 204-(3-Methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

The title compound was prepared from4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402mmol) and m-anisidine (45 μl, 0.402 mmol) similar to Example 13 andisolated as a tan solid (154 mg). ¹H NMR (CDCl₃): 8.23 (d, J=9.0 Hz,2H), 7.34 (s, 1H), 7.25–7.16 (m, 4H), 6.92–6.89 (m, 1H), 6.75 (s, 1H),6.69–6.65 (m, 1H), 4.51 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 2.40 (s,3H).

EXAMPLE 21 4-(2,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and2,5-dimethoxyaniline similar to Example 13 and isolated as a tan oil(116 mg, 74%). ¹H NMR (CDCl₃): 8.78–8.76 (m, 1H), 8.44 (d, J=7.8 Hz,1H), 7.81 (d, J=2.7 Hz, 1H), 7.79–7.74 (m, 1H). 7.32–7.28 (m, 2H), 6.78(d, J=9.3 Hz, 1H), 6.60 (s, 1H), 6.53 (dd, J=3.0, 8.7 Hz, 1H), 3.77 (d,J=3.3 Hz, 6H), 2.48 (s, 3H).

EXAMPLE 22 4-(2,3-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and2,3-dimethoxyaniline (69 μl, 0.486 mmol) similar to Example 11 andisolated as a white solid (169 mg). ¹H NMR (CDCl₃): 8.85–8.82 (m, 1H),8.48 (d, J=7.8 Hz, 1H), 7.87–7.82 (m, 1H), 7.54 (d, J=7.5 Hz, 1H),7.40–7.35 (m, 2H), 7.10 (t, J=8.4 Hz, 1H), 6.73 (d, J=1.5 Hz, 1H), 7.00(s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.53 (s, 3H).

EXAMPLE 23 4-(3-Benzyloxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and3-benzyloxyaniline (97 mg, 0.486 mmol) similar to Example 13 andisolated as a yellow oil (161 mg, 90%). ¹H NMR (CDCl₃): 8.78–8.76 (m,1H), 8.48–8.45 (m, 1H), 7.79–7.74 (m, 1H), 7.68 (s, 1H), 7.42–7.29 (m,6H), 7.24 (t, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J=0.8, 8.0 Hz, 1H),6.77–6.74 (m, 1H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H).

EXAMPLE 24 4-(3-Methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) andm-toluidine (52 μl, 0.486 mmol) similar to Example 13 and isolated as apale yellow oil (132 mg, 99%). ¹H NMR (CDCl₃): 8.76–8.74 (m, 1H),8.43–8.40 (m, 1H), 7.78–7.72 (m, 1H), 7.55 (s, 1H), 7.31–7.08 (m, 4H),6.92 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 2.41 (s, 3H), 2.30 (s, 3H).

EXAMPLE 25 4-(3-Ethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) andm-phenetidine (65 μl, 0.486 mmol) similar to Example 11 and isolated asa light tan solid (1116 mg, 78%). ¹H NMR (CDCl₃): 8.86–8.83 (m, 1H),8.50 (d, J=8.1 Hz, 1H), 7.89–7.83 (m, 1H), 7.42–7.38 (m, 1H), 7.35–7.30(m, 1H), 7.09 (s, 1H), 6.96–6.84 (m, 2H), 6.76 (d, J=3.3 Hz, 1H), 6.71(s, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.47 (t, J=7.1 Hz, 3H).

EXAMPLE 26 4-(3-Cyanoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and3-aminobenzonitrile (57 mg, 0.486 mmol) similar to Example 11 andisolated as a pale white solid (107 mg, 76%). ¹H NMR (DMSO-d₆): 10.14(s, 1H), 8.78–8.75 (m, 1H), 8.56 (s, 1H), 8.32 (d, J=7.8 Hz, 1H),8.04–7.96 (m, 2H), 7.60–7.47 (m, 3H), 6.75 (s, 1H), 2.47 (s, 3H).

EXAMPLE 27 4-(3-Acetophenoneanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and3-aminobenzophenone (96 mg, 0.486 mmol) similar to Example 11 andisolated as a light yellow solid (137 mg, 77%). ¹H NMR (DMSO-d₆): 10.76(s, 1H), 8.78 (d, J=3.9 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.7 Hz, 1H),8.08 (d, J=9.3 Hz, 1H), 8.02–7.97 (m, 1H), 7.81 (d, J=7.5 Hz, 2H),7.68–7.51 (m, 6H), 6.85 (s, 1H), 2.5 (s, 3H).

EXAMPLE 28 4-(3-Fluoroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and3-fluoroaniline (47 μl, 0.486 mmol) similar to Example 11 and isolatedas a light brown solid (74 mg, 54%). ¹H NMR (CDCl₃): 8.83 (d, J=4.8 Hz,1H), 8.47 (d, J=9 Hz, 1H), 7.88 (m, 1H), 7.44–7.30 (m, 4H), 7.18–7.14(m, 1H), 6.92–6.86 (m, 1H), 6.80 (s, 1H), 2.55 (s, 3H).

EXAMPLE 29 4-(2-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) ando-anisidine (27 μl, 0.243 mmol) similar to Example 13 and isolated as apale white solid (40 mg, 56%). ¹H NMR (CDCl₃): 8.82–8.80 (m, 1H), 8.46(d, J=8.1 Hz, 1H), 7.90 (dd, J=1.4, 7.7 Hz, 1H), 7.84–7.78 (m, 1H),7.36–7.32 (m, 1H), 7.28 (s, 1H), 7.18–6.98 (m, 2H), 6.92 (dd, J=1.8, 8.0Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 2.50 (s, 3H).

EXAMPLE 304-(3-Trifluoromethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-aminobenzotrifluoride (30 μl, 0.243 mmol) similar to Example 11 andisolated as a pale white solid (74 mg, 93%). ¹H NMR (CDCl₃): 8.84–8.82(m, 1H), 8.49–8.45 (m, 1H), 7.95 (s, 1H), 7.90–7.85 (m, 1H), 7.62 (d,J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.45–7.40 (m, 2H), 6.78 (s, 1H),2.55 (s, 3H).

EXAMPLE 31 4-(3-Acetoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-aminoacetophenone (33 mg, 0.243 mmol) similar to Example 11 andisolated as a white solid (60 mg, 81%). ¹H NMR (CDCl₃): 8.83 (d, J=4.5Hz, 1H), 8.50 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 7.89–7.83 (m, 1H), 7.75(d, J=7.8 Hz, 1H), 7.61–7.48 (m, 2H), 7.41–7.37 (m, 1H), 7.12 (s, 1H),6.61 (s, 1H), 2.65 (s, 3H), 2.53 (s, 3H).

EXAMPLE 324-(3-Trifluoromethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-(trifluoromethoxy)aniline (65 μl, 0.243 mmol) similar to Example 11and isolated as a pale white solid (78 mg, 93%). ¹H NMR (DMSO-d₆): 9.95(s, 1H), 8.74 (s, 1H), 8.31 (d, J=9.3 Hz, 2H), 7.95 (t, J=7.7 Hz, 1H),7.65 (d, J=8.4 Hz, 1H), 7.53–7.43 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.71(s, 1H), 2.44 (s, 3H).

EXAMPLE 33 4-(3-Ethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-ethylaniline (60 μl, 0.243 mmol) similar to Example 13 and isolated asan tan oil (69 mg, 98%). ¹H NMR (CDCl₃): 8.81–8.79 (m, 1H), 8.48–8.45(m, 1H), 7.84–7.78 (m, 1H), 7.42 (s, 1H), 7.37–7.29 (m, 2H), 7.18 (s,1H), 7.16 (d, J=1.5 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 2.66(q, J=7.5 Hz, 2H), 2.47 (s, 3H), 1.25 (t, J=7.5 Hz, 3H).

EXAMPLE 34 4-(3-Nitroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-nitroaniline (34 mg, 0.243 mmol) similar to Example 11 as a yellowsolid (65 mg, 87%). ¹H NMR (DMSO-d₆): 10.17 (s, 1H), 9.18 (s, 1H), 8.77(d, J=4.8 Hz, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.98(t, J=6.9 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (t, J=8.3 Hz, 1H),7.55–7.51 (m, 1H), 6.74 (s, 1H), 2.47 (s, 3H).

EXAMPLE 35 4-(3-Methylthioanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-(methylthio)aniline (30 μl, 0.243 mmol) similar to Example 13 andisolated as a pink oil (67 mg, 89%). ¹H NMR (CDCl₃): 8.77–8.74 (m, 1H),8.44–8.41 (m, 1H), 7.81–7.75 (m, 1H), 7.46 (s, 1H), 7.34–7.28 (m, 2H),7.23 (t, J=8.1 Hz, 1H), 7.09–7.06 (m, 1H), 7.00–6.97 (m, 1H), 6.55 (d,J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).

EXAMPLE 36 4-(3-Dimethylaminoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) andN,N-dimethyl-m-phenylenediamine (51 mg, 0.243 mmol) similar to Example13 and isolated as a dark green oil (49 mg, 66%). ¹H NMR (CDCl₃):8.82–8.79 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 7.84–7.78 (m, 1H), 7.37–7.21(m, 3H), 6.68–6.66 (m, 3H), 6.58–6.54 (m, 1H), 2.96 (s, 6H), 2.46 (s,3H).

EXAMPLE 37 4-(3-Isopropylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-isopropylaniline (33 μl, 0.243 mmol) similar to Example 13 andisolated as a gray oil (70 mg, 95%). ¹H NMR (CDCl₃): 8.79–8.77 (m, 1H),8.47–8.43 (m, 1H), 7.81–7.75 (m, 1H), 7.35–7.25 (m, 3H), 7.17–7.12 (m,2H), 7.02 (d, J=7.5 Hz, 1H), 2.93–2.84 (m, 1H), 2.45 (s, 3H), 1.24 (d,J=6.9 Hz, 6H).

EXAMPLE 384-(2,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385mmol) and 2,5-dimethoxyaniline (59 mg, 0.385 mmol) similar to Example 13and isolated as a greenish-yellow solid (24 mg, 17%). ¹H NMR (CDCl₃):9.67–9.66 (m, 1H), 8.74–8.70 (m, 2H), 8.02 (s, 1H), 7.44–7.39 (m, 1H),6.91 (s, 1H), 7.67 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.65 (dd, J=3.0, 9.0Hz, 1H), 3.86 (d, J=7.2 Hz, 6H).

EXAMPLE 394-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402mmol) and 2,5-dimethoxyaniline (62 mg, 0.402 mmol) similar to Example 13and isolated as a pale white solid (65 mg, 45%). ¹H NMR (CDCl₃): 8.30(d, J=3.0 Hz, 1H), 8.26–8.23 (m, 2H), 7.37–7.25 (m, 3H), 6.81 (d, J=9.0Hz, 1H), 6.73 (s, 1H), 6.55 (dd, J=3.0, 8.7 Hz, 1H), 4.52 (d, J=0.9 Hz,2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H).

EXAMPLE 40 4-(3-Methoxy-phenoxy)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3-methoxyphenol (27 μl, 0.243 mmol) similar to Example 13 and isolatedas a white oil (24 mg, 34%). ¹H NMR (CDCl₃): 8.79–8.76 (m, 1H),8.26–8.23 (m, 1H), 7.75–7.69 (m, 1H), 7.33–7.28 (m, 2H), 6.82–6.72 (m,3H), 6.58 (s, 1H), 3.77 (s, 3H), 2.58 (s, 3H).

EXAMPLE 414-(3-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and m-anisidine (22 μl, 0.193 mmol) similar to Example 13 andisolated as a yellow solid (31 mg, 46%). ¹H NMR (CDCl₃): 8.77–8.75 (m,2H), 8.28–8.25 (m, 2H), 7.36 (t, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.03 (s,1H), 6.98–6.96 (m, 2H), 6.83–6.81 (m, 1H), 3.84 (s, 3H).

EXAMPLE 424-(2,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2,5-dimethoxyaniline (32 mg, 0.193 mmol) similar to Example 13and isolated as a light tan solid (15 mg, 21%). ¹H NMR (CDCl₃): 8.79(dd, J=1.8, 4.8 Hz, 2H), 8.31 (dd, J=1.8, 4.8 Hz, 2H), 8.02 (bs, 1H),7.59 (s, 1H), 6.98 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.69 (dd, J=2.9, 9.2Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).

EXAMPLE 43 4-(2,5-Dimethoxyanilino)-5-methoxy-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (50 mg, 0.226 mmol) and2,5-dimethoxyaniline (35 mg, 0.226 mmol) similar to Example 11 andisolated as a gray solid (46 mg, 61%). ¹H NMR (CDCl₃): 8.77–8.74 (m,1H), 8.72 (d, J=3.0 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.10 (s, 1H), 8.03(s, 1H), 7.83–7.77 (m, 1H), 7.33–7.29 (m, 1H), 6.84 (d, J=8.7 Hz, 1H),6.56 (dd, J=3.0, 8.7 Hz, 1H), 4.04 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H).

EXAMPLE 444-(3-Methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine (50mg, 0.196 mmol) and m-anisidine (22 μl, 0.196 mmol) similar to Example11 and isolated as a white solid (29 mg, 43%). ¹H NMR (CDCl₃): 8.10 (s,1H), 7.28 (t, J=8.1 Hz, 1H), 6.97 (s, 2H), 6.90 (d, J=7.5 Hz, 1H), 6.85(s, 1H), 6.73–6.70 (m, 1H), 4.52 (s, 2H), 3.82 (s, 3H), 3.45 (s, 3H),2.81 (s, 3H).

EXAMPLE 454-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine (50mg, 0.196 mmol) and 2,5-dimethoxyaniline (33 mg, 0.196 mmol) similar toExample 11 and isolated as a gray solid (33 mg, 45%). ¹H NMR (CDCl₃):8.11 (s, 1H), 7.96 (s, 1H), 7.36 (s, 1H), 6.84–6.81 (m, 2H), 6.56 (dd,J=3.0, 9.0 Hz, 1H), 4.56 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.48 (s,3H), 2.80 (s, 3H).

EXAMPLE 46 6-Morpholino-4-(3-methoxyanilino)-2-phenyl-pyrimidine

A mixture of 4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181mmol), m-anisidine (20 μl, 0.181 mmol) and aqueous 2N HCl (150 μl) inwater:ethanol (1:1, 10 ml) was refluxed for 5 days. The mixture wascooled to room temperature and basified with aqueous 2N NaOH to pH10–12. The mixture was extracted with ethyl acetate (50 ml), which waswashed with water (2×25 ml), aqueous saturated NaCl, and dried overanhydrous sodium sulfate. The ethyl acetate solution was concentrated invacuo and isolated as a yellow solid (6 mg, 9%). ¹H NMR (CDCl₃):8.40–8.37 (m, 2H), 7.46–7.43 (m, 3H), 7.31–7.25 (m, 2H), 7.00 (t, J=2.3Hz, 1H), 6.91 (dd, J=1.7, 8.0 Hz, 1H), 6.70–6.67 (m, 2H), 3.83 (s, 3H),3.81–3.63 (m, 8H).

EXAMPLE 47 6-Morpholino-4-(2,5-dimethoxyanilino)-2-phenyl-4-pyrimidine

The title compound was prepared from a mixture of4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol) and2,5-dimethoxyaniline (28 mg, 0.181 mmol) similar to Example 46 andisolated as a brown oil (6 mg, 8%). ¹H NMR (DMSO-d₆): 8.49 (bs, 1H),8.33–8.30 (m, 2H), 7.93 (bs, 1H), 6.22 (s, 1H), 7.52–7.50 (m, 3H), 6.99(dd, J=8.7 Hz, 1H), 6.61 (dd, J=2.7, 8.7 Hz, 1H), 3.81 (s, 3H), 3.76 (s,3H), 3.74–3.70 (m, 8H).

EXAMPLE 484-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine (50mg, 0.196 mmol) and 2-chloro-5-methoxyaniline (38 mg, 0.196 mmol)similar to Example 13 and isolated as a white solid (33 mg, 45%). ¹H NMR(CDCl₃): 8.14 (s, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H),7.22 (s, 1H), 6.86 (s, 1H), 6.64 (dd, J=3.0, 9.3 Hz, 1H), 4.60 (s, 2H),3.88 (s, 3H), 3.52 (s, 3H), 2.84 (s, 3H).

EXAMPLE 494-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine (50mg, 0.196 mmol) and 5-methoxy-2-methylaniline (27 mg, 0.196 mmol)similar to Example 13 and isolated as a tan oil (42 mg, 60%). ¹H NMR(CDCl₃): 8.12 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H),6.89 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 6.56 (s, 1H), 4.50 (s, 2H),3.80 (s, 3H), 3.44 (s, 3H), 2.83 (s, 3H), 2.21 (s, 3H).

EXAMPLE 504-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-chloro-5-methoxyaniline (37 mg, 0.193 mmol) similar toExample 13 and isolated as a white solid (10 mg, 14%). ¹H NMR (CDCl₃):9.70 (d, J=1.8 Hz, 1H), 8.77–8.74 (m, 2H), 7.86 (s, 1H), 7.67 (s, 1H),7.48–7.44 (m, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H), 6.76 (dd,J=3.0, 9.3 Hz, 1H), 3.90 (s, 3H).

EXAMPLE 514-(5-Methoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-methoxy-2-methylaniline (26 mg, 0.193 mmol) similar toExample 13 and isolated as a tan solid (8 mg, 12%). ¹H NMR (CDCl₃): 9.72(d, J=0.6 Hz, 1H), 8.74–8.68 (m, 2H), 7.70 (s, 1H), 7.44–7.40 (m, 1H),7.27 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.85 (dd, J=2.7, 8.7 Hz, 1H),6.64 (s, 1H), 3.83 (s, 3H), 2.24 (s, 3H).

EXAMPLE 524-(2-Chloro-5-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and2-chloro-5-methoxyaniline (47 mg, 0.243 mmol) similar to Example 13 andisolated as a tan oil (35 mg, 44%). ¹H NMR (CDCl₃): 8.82–8.80 (m, 1H),8.47 (d, J=7.8 Hz, 1H), 7.86–7.81 (m, 1H), 7.77 (d, J=2.7 Hz, 1H),7.41–7.36 (m, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 6.68 (s, 1H), 6.65 (dd,J=2.7, 8.7 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H).

EXAMPLE 534-(5-Methoxy-2-methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and5-methoxy-2-methylaniline (33 mg, 0.243 mmol) similar to Example 13 andisolated as a tan oil (45 mg, 60%). ¹H NMR (CDCl₃): 8.78–8.77 (m, 1H),8.44 (d, J=8.1 Hz, 1H), 7.81–7.75 (m, 1H), 7.34–7.30 (m, 1H), 7.16 (d,J=8.4 Hz, 1H), 6.91 (d, J=2.7 Hz, 2H), 6.72 (dd, J=2.7, 8.7 Hz, 1H),6.30 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).

EXAMPLE 544-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-chloro-5-methoxyaniline (38 mg, 0.193 mmol) similar toExample 13 and isolated as a pink solid (18 mg, 25%). ¹H NMR (CDCl₃):8.82 (dd, J=1.4, 4.7 Hz, 2H), 8.32 (dd, J=1.7, 4.4 Hz, 2H), 7.84 (d,J=2.1 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 6.77(dd, J=3.3, 9.3 Hz, 1H), 3.90 (s, 3H).

EXAMPLE 554-(5-Methoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-methoxy-2-methylaniline (27 mg, 0.193 mmol) similar toExample 13 and isolated as a pink solid (23 mg, 33%). ¹H NMR (CDCl₃):8.77 (d, J=5.7 Hz, 2H), 8.27 (d, J=5.7 Hz, 2H), 7.32 (s, 1H), 7.26 (d,J=9.0 Hz, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H),3.82 (s, 3H), 2.24 (s, 3H).

EXAMPLE 564-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201mmol) and 2-chloro-5-methoxyaniline (39 mg, 0.201 mmol) similar toExample 13 and isolated as a white solid (18 mg, 24%). ¹H NMR (CDCl₃):8.27–8.25 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.33(s, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 6.66 (dd, J=3.0, 9.0 Hz, 1H), 4.59(s, 2H), 3.93 (s, 3H), 3.58 (s, 3H), 2.47 (s, 3H).

EXAMPLE 574-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201mmol) and 5-methoxy-2-methylaniline (28 mg, 0.201 mmol) similar toExample 13. ¹H NMR (CDCl₃): 8.20–8.16 (m, 2H), 7.35 (t, J=7.5 Hz, 1H),7.28 (s, 1H), 7.18 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.73 (dd, J=2.7, 8.4Hz, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.49 (s, 2H), 3.82 (s, 3H), 3.47(s, 3H), 2.44 (s, 3H), 2.23 (s, 3H).

EXAMPLE 584-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol), 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (97 mg,0.386 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml)was refluxed for 24 h. The mixture was cooled to room temperature,extracted with ethyl acetate (50 ml) and washed with water (1×25 ml).The ethyl acetate solution was acidified with aqueous 2N HCl (1×25 ml).The resulting precipitate was collected by filtration, washed with waterand isolated as a pale white solid (59 mg, 64%). ¹H NMR (DMSO-d₆): 10.54(s, 1H), 9.44 (d, J=2.1 Hz, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.62–8.58(m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.65 (t, J=8.3 Hz,1H), 7.59–7.54 (m, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 3.81 (s,3H).

EXAMPLE 594-[3-(2-Methyl-pyrimidin-4-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-(3-aminophenyl)-2-methylpyrimidine (71 mg, 0.386 mmol)similar to Example 58. The mixture was extracted with ethyl acetate (50ml), washed with water (1×25 ml) and with aqueous 2N HCl (1×25 ml). Theacidic aqueous solution was basified with aqueous 2N NaOH to pH 10–12.The resulting precipitate was filtered, washed with water and isolatedas a light tan solid (18 mg, 23%). ¹H NMR (CDCl₃): 9.71 (d, J=2.4 Hz,1H), 8.77–8.72 (m, 3H), 8.38 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.69–7.54(m, 4H), 7.45–7.41 (m, 1H), 6.95 (s, 1H), 2.83 (s, 3H).

EXAMPLE 604-(3-Phenylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58. Themixture was basified with aqueous 2N NaOH to pH 10–12. The resultingprecipitate was collected by filtration, washed with excesswater:ethanol (1:1) and isolated as a light brown solid (64 mg, 85%). ¹HNMR (CDCl₃): 9.67 (s, 1H), 8.75 (d, J=5.4 Hz, 2H), 7.68 (s, 1H),7.63–7.37 (m, 10H), 6.98 (s, 1H).

EXAMPLE 614-[3-(3-Nitrophenyl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-amino-3′-nitrobiphenyl (83 mg, 0.386 mmol) similar toExample 58 and isolated as a light tan solid (65 mg, 77%). ¹H NMR(DMSO-d₆): 13.00 (s, 1H), 11.94 (s, 1H), 11.23 (d, J=4.5 Hz, 1H), 11.11(d, J=8.1 Hz, 1H), 10.97 (s, 1H), 10.78 (s, 1H), 10.75 (s, 1H), 10.69(d, J=8.1 Hz, 1H), 10.35–10.28 (m, 2H), 10.14–10.04 (m, 3H), 9.67 (s,1H).

EXAMPLE 624-[3-(2,3,4,5,6-Pentafluorophenoxy)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-(2,3,4,5,6-pentafluorophenoxy)aniline (106 mg, 0.386 mmol)similar to Example 58 and isolated as a yellow solid (65 mg, 68%). ¹HNMR (DMSO-d₆): 10.46 (s, 1H), 9.24 (s, 1H), 8.75 (dd, J=1.8, 4.8 Hz,1H), 8.56–8.52 (m, 1H), 7.77 (s, 1H), 7.59–7.55 (m, 1H), 7.50–7.41 (m,2H), 7.14 (s, 1H), 6.94–6.92 (m, 1H).

EXAMPLE 634-(2,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2,5-dimethoxyaniline (59 mg, 0.386 mmol) similar to Example 58and isolated as a light brown solid (36 mg, 50%). ¹H NMR (DMSO-d₆): 9.65(s, 1H), 8.76–8.73 (m, 1H), 8.32 (d, J=7.8 Hz, 2H), 8.03–7.97 (m, 1H),7.58–7.54 (m, 2H), 7.05 (d, J=9.0 Hz, 1H), 6.70 (dd, J=3.0, 8.7 Hz, 1H),3.84 (s, 3H), 3.82 (s, 3H).

EXAMPLE 644-[3-(2-Ethyl-1-phenyl-pyrazolin-5-one-3-yl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-(3-aminophenyl)-2-ethyl-1-phenyl-3-pyrazolin-5-one (54 mg,0.193 mmol) similar to Example 58 and isolated as a dark yellow solid(52 mg, 54%). ¹H NMR (DMSO-d₆): 10.61 (s, 1H), 9.52 (s, 1H), 8.83–8.81(m, 1H), 8.65 (dd, J=1.2, 7.5 Hz, 1H), 8.38 (s, 1H), 7.80 (d, J=7.8 Hz,1H), 7.68–7.48 (m, 7H), 7.37–7.33 (m, 1H), 7.22 (s, 1H), 5.97 (s, 1H),3.63 (q, J=6.6 Hz, 2H), 0.634 (t, J=6.6 Hz, 3H).

EXAMPLE 654-[3-(Phenylsulfone)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-aminodiphenylsulfone (90 mg, 0.386 mmol) similar to Example58 and isolated as a yellow solid (44 mg, 50%). ¹H NMR (CDCl₃): 9.68 (d,J=2.4 Hz, 1H), 9.16 (s, 1H), 8.78–8.74 (m, 1H), 8.71–8.69 (m, 1H), 8.61(s, 1H), 7.97 (d, J=7.2 Hz, 2H), 7.85–7.82 (m, 1H), 7.65 (d, J=7.5 Hz,1H), 7.56–7.42 (m, 5H), 6.94 (s, 1H).

EXAMPLE 664-[3-(N-phenylamide)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-aminobenzanilide (41 mg, 0.193 μmmol) similar to Example 58and isolated as a dark pink solid (41 mg, 49%). ¹H NMR (DMSO-d₆): 10.43(s, 1H), 10.24 (s, 1H), 9.39 (d, J=1.2 Hz, 1H), 8.62 (dd, J=1.5, 4.8 Hz,1H), 8.57–8.54 (m, 1H), 8.40 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.69 (d,J=8.4 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43–7.39(m, 1H), 7.25 (t, J=7.8 Hz, 2H), 7.06 (s, 1H), 7.02–6.97 (m, 1H).

EXAMPLE 674-(3-Phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-phenoxyaniline (71 mg, 0.386 mmol) similar to Example 58 andisolated as a pale white solid (33 mg, 42%). ¹H NMR (CDCl₃): 9.74 (d,J=2.1 Hz, 1H), 8.72–8.66 (m, 2H), 8.52 (bs, 1H), 7.45–7.37 (m, 4H),7.21–7.10 (m, 5H), 6.97 (s, 1H), 6.93 (dd, J=2.1, 8.1 Hz, 1H).

EXAMPLE 684-(2,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2,5-dimethylaniline (48 μl, 0.386 mmol) similar to Example 58and isolated as a light tan solid (14 mg, 21%). ¹H NMR (CDCl₃): 9.70(dd, J=0.8, 2.0 Hz, 1H), 8.74–8.70 (m, 1H), 8.67 (dd, J=1.8, 4.8 Hz,1H), 7.75 (s, 1H), 7.43–7.38 (m, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.19 (s,1H), 7.10 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 2.38 (s, 3H), 2.26 (s, 3H).

EXAMPLE 694-(3-Hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (89 mg, 0.344mmol) and 3-aminophenol (30 mg, 0.275 mmol) similar to Example 58 andisolated as a yellow solid (61 mg, 67%). ¹H NMR (DMSO-d₆): 10.40 (s,1H), 8.86 (dd, J=0.9, 5.1 Hz, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.32–8.26 (m,1H), 7.82–7.78 (m, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 7.23 (s, 1H), 7.19(d, J=7.5 Hz, 1H), 6.57 (dd, J=1.8, 9.0 Hz, 1H).

EXAMPLE 704-(3,4-Methylenedioxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar toExample 58 and isolated as a purple solid (24 mg, 35%). ¹H NMR (CDCl₃):8.85–8.83 (m, 1H), 8.57–8.54 (m, 1H), 7.90–7.84 (m, 1H), 7.45–7.41 (m,1H), 7.39 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.80 (s, 1H),6.77 (dd, J=2.1, 8.1 Hz, 1H), 6.05 (s, 2H).

EXAMPLE 714-(3,4-Methylenedioxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar toExample 58 and isolated as a dark brown solid (47 mg, 68%). ¹H NMR(CDCl₃): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.26 (dd, J=1.5, 4.5 Hz, 2H),7.06 (s, 1H), 6.93 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.81 (dd, J=2.1, 8.1Hz, 1H), 6.81 (s, 1H), 6.06 (s, 2H).

EXAMPLE 724-(3,4-Methylenedioxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar toExample 58 and isolated as a light brown solid (37 mg, 53%). ¹H NMR(CDCl₃): 9.63 (dd, J=0.9, 1.8 Hz, 1H), 8.73–8.68 (m, 2H), 7.43–7.39 (m,1H), 6.93 (s, 1H), 6.88 (d, J=8.1 Hz, 2H), 6.83 (dd, J=1.8, 8.1 Hz, 1H),6.77 (s, 1H), 6.06 (s, 2H).

EXAMPLE 73 4-(3-Methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

a. 4-Chloro-2-phenyl-6-(trifluoromethyl)pyrimidine: A mixture of4-hydroxy-2-phenyl-6-(trifluoromethyl)pyrimidine (1.5 g, 6.24 mmol) andphosphorus oxychloride (25 ml) was refluxed for 3 h. The mixture wascooled to room temperature and then rotary evaporated to dryness. Theresidual was extracted with ethyl acetate (100 ml), washed with water(2×50 ml), and then with aqueous saturated sodium chloride (1×50 ml).The ethyl acetate solution was dried over anhydrous sodium sulfate andthen rotary evaporated to dryness to give a pale white solid (1.6 g,99%). ¹H NMR (DMSO-d₆): 8.39–8.36 (m, 2H), 8.26 (s, 1H), 7.66–7.57 (m,3H).

b. 4-(3-Methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine: Amixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol), m-anisidine (33 μl, 0.290 mmol) and aqueous 2N HCl (150 μl) inwater:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooledto room temperature and then basified with aqueous 2N NaOH to pH 10–12.The mixture was extracted with ethyl acetate (75 ml), washed with water(2×25 ml), and then with aqueous saturated sodium chloride (1×25 ml).The ethyl acetate solution was dried over anhydrous sodium sulfate andthen rotary evaporated to dryness. The residual was purified by columnchromatography and isolated as a light gray solid (15 mg, 23%). ¹H NMR(CDCl₃): 8.47–8.44 (m, 2H), 7.51–7.46 (m, 3H), 7.34 (t, J=8.1 Hz, 1H),7.16 (s, 1H), 7.10 (s, 1H), 6.98 (dd, J=1.5, 7.8 Hz, 1H), 6.89 (s, 1H),6.81–6.77 (m, 1H), 3.85 (s, 3H).

EXAMPLE 744-(3-Methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

a. 4-Chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine: A mixture of4-hydroxy-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (2.0 g, 8.26mmol) and phosphorus oxychloride (30 ml) was refluxed for 3 h. Themixture was cooled to room temperature and then rotary evaporated todryness. The residual was purified by column chromatography and isolatedas a tan solid (1.8 g, 84%). ¹H NMR (DMSO-d₆): 9.54 (d, J=1.5 Hz, 1H),8.92 (dd, J=1.5, 2.4 Hz, 1H), 8.90 (d, J=2.4 Hz, 1H), 8.48 (s, 1H).

b. 4-(3-Methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine: Amixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.192 mmol), m-anisidine (32 μl, 0.288 mmol) and aqueous 2N HCl (150μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture wascooled to room temperature and then basified with aqueous 2N NaOH to pH10–12. The mixture was extracted with ethyl acetate (75 ml), washed withwater (2×25 ml), and then with aqueous saturated sodium chloride (1×25ml). The ethyl acetate solution was dried over anhydrous sodium sulfateand then rotary evaporated to dryness. The residual was purified bycolumn chromatography and isolated as a yellow solid (38 mg, 57%). ¹HNMR (CDCl₃): 9.74 (d, J=1.2 Hz, 1H), 8.74 (dd, J=1.5, 2.4 Hz, 1H), 8.71(d, J=2.4 Hz, 1H), 8.04 (s, 1H), 7.34 (t, J=8.1 Hz, 1H), 7.07 (s, 1H),7.01 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.82 (dd, J=2.7, 8.4 Hz, 1H), 3.84(s, 3H).

EXAMPLE 754-(2,5-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg,0.193 mmol), 2,5-dimethoxyaniline (44 mg, 0.290 mmol) and aqueous 2N HCl(150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. Themixture was cooled to room temperature and then basified with aqueous 2NNaOH to pH 10–12. The resulting precipitate was filtered, washed withwater, water:ethanol (2:1) and dried under vacuo to give a gray solid(36 mg, 50%). ¹H NMR (CDCl₃): 8.51–8.48 (m, 2H), 8.14 (s, 1H), 7.51–7.48(m, 4H), 6.89 (s, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.66 (dd, J=3.0, 8.7 Hz,1H), 3.90 (s, 3H), 3.87 (s, 3H).

EXAMPLE 764-(2,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.192 mmol), 2,5-dimethoxyaniline and aqueous 2N HCl (150 μl) inwater:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooledto room temperature and then basified with aqueous 2N NaOH to pH 10–12.The resulting precipitate was filtered, washed with water, water:ethanol(2:1) and isolated as a green-yellow solid (46 mg, 64%). ¹H NMR (CDCl₃):9.74 (d, J=1.5 Hz, 1H), 8.79 (dd, J=1.8, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz,1H), 7.80 (bs, 1H), 7.70 (s, 1H), 7.07 (s, 1H), 6.91 (d, J=9.3 Hz, 1H),6.72 (dd, J=3.0, 9.0 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H).

EXAMPLE 774-(3,4-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and3,4-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example 75. Themixture was extracted with ethyl acetate (75 ml), washed with water(2×25 ml), washed with aqueous saturated NaCl (1×25 ml), and dried overanhydrous sodium sulfate. The ethyl acetate solution was rotaryevaporated to dryness. The residual was purified by columnchromatography and isolated as a yellow oil (35 mg, 48%). ¹H NMR(CDCl₃): 8.45–8.42 (m, 2H), 7.50–7.44 (m, 3H), 7.25 (s, 1H), 7.02 (s,1H), 6.90 (s, 2H), 6.74 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).

EXAMPLE 784-(3,4-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192mmol), 3,4-dimethoxyaniline (44 mg, 0.288 mmol) similar to Example 76and isolated as a yellow solid (52 mg, 72%). ¹H NMR (CDCl₃): 9.74 (d,J=1.2 Hz, 1H), 8.78 (dd, J=1.2, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H),7.36 (s, 1H), 6.96–6.90 (m, 3H), 6.88 (s, 1H), 3.94 (s, 3H), 3.91 (s,3H).

EXAMPLE 794-(5-Methoxy-2-methylanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and5-methoxy-2-methylaniline (40 mg, 0.290 mmol) similar to Example 77 andisolated as a tan oil (33 mg, 48%). ¹H NMR (CDCl₃): 8.46–8.42 (m, 2H),7.50–7.46 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.92(s, 1H), 6.80 (dd, J=2.6, 8.6 Hz, 1H), 6.61 (s, 1H), 3.81 (s, 3H), 2.22(s, 3H).

EXAMPLE 804-(5-Methoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192mmol), 5-methoxy-2-methylaniline (40 mg, 0.288 mmol) similar to Example76 and isolated as a yellow solid (40 mg, 58%). ¹H NMR (CDCl₃): 9.75 (d,J=1.2 Hz, 1H), 8.79 (dd, J=1.5, 2.4 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H),7.28 (d, J=4.5 Hz, 1H), 7.24 (s, 1H), 6.89 (d, J=2.7 Hz, 1H), 6.86 (dd,J=2.7, 8.4 Hz, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 2.22 (s, 3H).

EXAMPLE 814-(2-Chloro-5-methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg,0.193 mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.290mmol) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixturewas cooled to room temperature and then basified with aqueous 2N NaOH topH 10–12. The resulting precipitate was filtered, washed with water,water:ethanol (2:1) and isolated as a brown solid (28 mg, 38%). ¹H NMR(CDCl₃): 8.50–8.47 (m, 2H), 7.99 (d, J=3.0 Hz, 1H), 7.53–7.47 (m, 3H),7.36 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 6.91 (s, 1H), 6.71 (dd, J=3.0, 9.0Hz, 1H), 3.88 (s, 3H).

EXAMPLE 824-(2-Chloro-5-methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.288 mmol)similar to Example 76 and isolated as a tan solid (41 mg, 56%). ¹H NMR(CDCl₃): 9.75 (d, J=1.2 Hz, 1H), 8.79 (dd, J=1.7, 2.6 Hz, 1H), 8.73 (d,J=2.4 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.04(s, 1H), 6.78 (dd, J=2.9, 8.9 Hz, 1H), 3.89 (s, 3H).

EXAMPLE 834-(3,4-Methylenedioxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and3,4-methylenedioxyaniline (40 mg, 0.290 mmol) similar to Example 77 andisolated as a tan solid (16 mg, 23%). ¹H NMR (CDCl₃): 8.44–8.40 (m, 2H),7.50–7.45 (m, 3H), 7.02 (s, 1H), 6.91 (s, 1H), 6.85 (d, J=8.1 Hz, 1H),6.78 (dd, J=2.0, 8.3 Hz, 1H), 6.71 (s, 1H), 6.03 (s, 2H).

EXAMPLE 844-(3,4-Methylenedioxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192mmol) and 3,4-methylenedioxyaniline (39 mg, 0.288 mmol) similar toExample 76 and isolated as a pink solid (21 mg, 30%). ¹H NMR (CDCl₃):9.72 (d, J=1.2 Hz, 1H), 8.76 (dd, J=1.5, 2.7 Hz, 1H), 8.71 (d, J=2.7 Hz,1H), 7.60 (s, 1H), 6.88 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.83 (s, 1H),6.78 (dd, J=1.8, 8.1 Hz, 1H), 6.05 (s, 2H).

EXAMPLE 854-(2-Methoxy-5-phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar toExample 58 and isolated as a tan solid (46 mg, 54%). ¹H NMR (CDCl₃):9.57 (dd, J=1.1, 2.3 Hz, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 8.42–8.38(m, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.38–7.31 (m, 2H), 7.25–7.21 (m,1H), 7.11 (t, J=1.2 Hz, 1H), 7.09–7.03 (m, 2H), 6.91 (d, J=8.7 Hz, 2H),6.82 (dd, J=2.7, 8.7 Hz, 1H), 3.91 (s, 3H).

EXAMPLE 864-[2-Methyl-5-(carboxymethylester)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-amino-4-methylbenzoate (48 mg, 0.290 mmol) similar toExample 58 and isolated as a yellow solid (2 mg, 3%). ¹H NMR (CDCl₃):9.61 (s, 1H), 8.69–8.65 (m, 2H), 8.22 (s, 1H), 7.90 (dd, J=1.8, 7.8 Hz,1H), 7.40–7.35 (m, 2H), 7.14 (s, 1H), 6.59 (s, 1H), 3.91 (s, 3H), 2.35(s, 3H).

EXAMPLE 874-(2-Methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar toExample 58 and isolated as a yellow solid (41 mg, 59%). ¹H NMR (CDCl₃):9.66 (d, J=1.8 Hz, 1H), 8.74–8.70 (m, 2H), 7.98 (s, 1H), 7.55 (s, 1H),7.44–7.40 (m, 1H), 6.99–6.95 (m, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 3.89(s, 3H), 2.40 (s, 3H).

EXAMPLE 884-(5-Fluoro-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-fluoro-2-methylaniline (36 mg, 0.290 mmol) similar toExample 58 and isolated as a tan solid (4 mg, 6%). ¹H NMR (CDCl₃): 9.71(dd, J=0.80, 2.3 Hz, 1H), 8.74–8.71 (m, 1H), 8.68 (dd, J=1.7, 5.0 Hz,1H), 7.72 (s, 1H), 7.44–7.39 (m, 1H), 7.33–7.28 (m, 2H), 7.02–6.95 (m,1H), 6.67 (s, 1H), 2.29 (s, 3H).

EXAMPLE 894-(2-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-amino-4-methoxybenzotrifluoride (55 mg, 0.290 mmol) similarto Example 58 and isolated as a yellow solid (56 mg, 70%). ¹H NMR(CDCl₃): 9.66 (dd, J=0.6, 2.1 Hz, 1H), 8.95 (s, 1H), 8.75 (dd, J=1.8,4.8 Hz, 1H), 8.73–8.69 (m, 1H), 7.67 (s, 1H), 7.46–7.42 (m, 1H),7.41–7.37 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 3.99 (s, 3H).

EXAMPLE 904-(2-Methyl-5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (500mg, 1.93 mmol), 2-methyl,5-nitroaniline (441 mg, 2.90 mmol), and 2N HCl(1.5 ml) in water:ethanol (1:1, 100 ml) was refluxed for 48 h. Themixture was cooled to room temperature and basified with aqueous 2N NaOHto pH 10–12. The resulting precipitate was filtered, washed with waterand water:ethanol (2:1). The product was dried under vacuo and thenwashed with chloroform to give a yellow solid (136 mg, 19%). ¹H NMR(DMSO-d₆): 9.84 (s, 1H), 9.41 (s, 1H), 8.99 (s, 1H), 8.73 (d, J=4.2 Hz,1H), 8.57 (d, J=7.8 Hz, 1H), 8.02 (dd, J=1.8, 7.8, 1H), 7.61 (d, J=8.1Hz, 1H), 7.58–7.54 (m, 1H), 7.39 (s, 1H), 2.45 (s, 3H).

EXAMPLE 914-(5-Amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

To a solution of4-(2-methyl,5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine(75 mg, 0.200 mmol) in anhydrous ethanol (10 ml) was added slowlyanhydrous tin chloride (152 mg, 0.800 mmol). The mixture was refluxedfor 1 h and then rotary evaporated to leave a brown oil. The brown oilwas basified with 2N NaOH to give a final pH of 8. The resultingprecipitate was filtered and washed with ethyl acetate. The aqueousphase and organic phase was combined, washed with water (1×20 ml) anddried over anhydrous sodium sulfate. The ethyl acetate was rotaryevaporated to dryness to give a dark yellow solid (33 mg, 44%). ¹H NMR(CDCl₃): 9.69–9.68 (m, 1H), 8.73–8.67 (m, 2H), 7.53 (s, 1H), 7.43–7.39(m, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J=2.7 Hz, 1H),6.61 (s, 1H), 3.01 (bs, 2H), 2.17 (s, 3H).

EXAMPLE 924-(3-Ethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25mg, 0.096 mmol), m-phenetidine (19 μl, 0.144 mmol), and 2N HCl (75 μl)in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture wascooled to room temperature and basified with aqueous 2N NaOH to pH10–12. The resulting precipitate was filtered, washed with water,water:ethanol (2:1) and dried to give a yellow solid (22 mg, 63%). ¹HNMR (CDCl₃): 8.88–8.85 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.93–7.88 (m,1H), 7.61 (s, 1H), 7.48–7.44 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.05 (s,1H), 6.89–6.81 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).

EXAMPLE 934-(3-Ethylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096mmol) and 3-ethylaniline (18 μl, 0.144 mmol) similar to Example 92 andisolated as a yellow oil (12 mg, 36%). ¹H NMR (CDCl₃): 8.84–8.82 (m,1H), 8.57–8.54 (m, 1H), 7.89–7.84 (m, 1H), 7.72 (s, 1H), 7.44–7.40 (m,1H), 7.34 (d, J=8.7 Hz, 1H), 7.14–7.11 (m, 3H), 7.01 (s, 1H), 2.69 (q,J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).

EXAMPLE 944-(5-Methoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096mmol) and 5-methoxy-2-methylaniline (20 mg, 0.144 mmol) similar toExample 92 and isolated as a yellow solid (18 mg, 52%). ¹H NMR (CDCl₃):8.85–8.82 (m, 1H), 8.59–8.56 (m, 1H), 7.90–7.84 (m, 1H), 7.45–7.40 (m,2H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J=2.6, 8.3 Hz, 1H),6.69 (s, 1H), 3.81 (s, 3H), 2.20 (s, 3H).

EXAMPLE 954-(2-Chloro-5-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096mmol) and 2-chloro-5-methoxyaniline (23 mg, 0.144 mmol) similar toExample 92 and isolated as a white solid (11 mg, 48%). ¹H NMR (CDCl₃):8.84–8.82 (m, 1H), 8.58–8.54 (m, 1H), 7.90–7.85 (m, 1H), 7.66 (s, 1H),7.60 (s, 1H), 7.46–7.41 (m, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.01 (s, 1H),6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.88 (s, 3H).

EXAMPLE 964-(3-Methylmercaptoanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096mmol) and 3-(methylmercapto)aniline (18 μl, 0.144 mmol) similar toExample 92 and isolated as a yellow solid (21 mg, 58%). ¹H NMR (CDCl₃):8.87–8.85 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 7.93–7.88 (m, 1H), 7.61 (s,1H), 7.48–7.44 (m, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.17–7.14(m, 1H), 7.10–7.06 (m, 1H), 7.01 (s, 1H), 2.52 (s, 3H).

EXAMPLE 974-(3-Hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol), 3-aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 μl) inwater:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooledto room temperature and the resulting crystals was filtered, washed withwater, with water:ethanol (2:1) and dried to give a tan crystals (22 mg,30%). ¹H NMR (DMSO-d₆): 10.17 (s, 1H), 9.36 (d, J=1.5 Hz, 1H), 8.72–8.66(m, 2H), 7.66–7.62 (m, 1H), 7.20 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.05(d, J=7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.45–6.41 (m, 1H).

EXAMPLE 984-(3-Hydroxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192mmol) and 3-aminophenol (31 mg, 0.288 mmol) similar to Example 97 andisolated as a tan solid (28 mg,). ¹H NMR (DMSO-d₆): 10.26 (s, 1H), 9.62(s, 1H), 9.51–9.50 (m, 1H), 8.87–8.83 (m, 2H), 7.30 (s, 1H), 7.23–7.21(m, 3H), 6.57–6.54 (m, 1H).

EXAMPLE 994-(3-Hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol), 3-aminophenol (32 mg, 0.290 mmol) similar to Example 97 andisolated as a yellow solid (37 mg, 52%). ¹H NMR (DMSO-d₆): 10.51 (s,1H), 8.98 (d, J=6.0 Hz, 2H), 8.54 (d, J=6.6 Hz, 2H), 7.32–7.21 (m, 5H),6.61–6.57 (m, 1H).

EXAMPLE 100 4-(2,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and2,4-dimethoxyaniline (56 mg, 0.365 mmol) similar to Example 92 andisolated as a purple crystal (52 mg, 64%). ¹H NMR (CDCl₃): 8.84–8.81 (m,1H), 8.48–8.44 (m, 1H), 7.86–7.80 (m, 1H), 7.60 (d, J=8.4 Hz, 1H),7.38–7.34 (m, 1H), 6.93 (s, 1H), 6.56–6.53 (m, 2H), 6.46 (s, 1H), 3.84(d, J=0.6 Hz, 3H), 3.83 (d, J=0.9 Hz, 3H), 2.48 (s, 3H).

EXAMPLE 101 4-(3,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and3,5-dimethoxyaniline (56 mg, 0.365 mmol) similar to Example 92 andisolated as a tan solid (21 mg, 26%). ¹H NMR (CDCl₃): 8.83–8.81 (m, 1H),8.49–8.46 (m, 1H), 7.86–7.80 (m, 1H), 7.39–7.35 (m, 1H), 6.99 (s, 1H),6.70 (s, 1H), 6.53 (d, J=2.4 Hz, 2H), 6.30 (t, J=2.3 Hz, 1H), 3.82 (s,6H), 2.51 (s, 3H).

EXAMPLE 1024-(2,5-Diethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol), 2,5-diethoxyaniline (52 mg, 0.290 mmol) and 2N HCl (150μl) in water:ethanol (3:1, 10 ml) was refluxed for 24 h. The mixture wascooled to room temperature and basified with aqueous 2N NaOH to pH10–12. The resulting precipitate was filtered and isolated as a yellowsolid (14 mg, 18%). ¹H NMR (CDCl₃): 9.67 (s, 1H), 8.74–8.71 (m, 2H),7.93 (s, 1H), 7.64 (s, 1H), 7.43–7.39 (m, 1H), 6.91 (s, 1H), 6.86 (d,J=9.3 Hz, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 4.13–4.04 (m, 4H),1.47–1.42 (m, 6H).

EXAMPLE 1034-(5-Carboxyl-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-amino-4-methoxybenzoic acid (48 mg, 0.290 mmol) similar toExample 92 and isolated as a white solid (50 mg, 64%). ¹H NMR (DMSO-d₆):9.78 (s, 1H), 9.49–9.48 (m, 1H), 9.08 (s, 1H), 8.74 (dd, J=1.5, 4.8 Hz,1H), 8.70–8.67 (m, 1H), 7.79 (dd, J=1.5, 4.8 Hz, 1H), 7.56–7.52 (m, 2H),7.23 (d, J=9.0 Hz, 1H), 3.97 (s, 3H).

EXAMPLE 1044-(3-Methoxybenzylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol) and 3-methoxybenzylamine (37 μl, 0.290 mmol) in 10 ml ofethanol was stirred at room temperature for 48 h. The mixture was rotaryevaporated to dryness and purified by preparative TLC with hexane:ethylacetate (3:1) to give a yellow solid (14 mg, 20%). ¹H NMR (CDCl₃):9.60–9.59 (m, 1H), 8.70–8.66 (m, 2H), 7.40–7.32 (m, 1H), 7.30 (d, J=7.8Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz,1H), 6.62 (s, 1H), 5.75 (bs, 1H), 4.73 (s, 2H), 3.79 (s, 3H).

EXAMPLE 1054-(5-Carboxyl-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-amino-4-hydroxybenzoic acid (44 mg, 0.290 mmol) similar toExample 92 and isolated as a brown solid (25 mg, 34%). ¹H NMR (DMSO-d₆):9.73 (s, 1H), 9.49 (d, J=1.5 Hz, 1H), 9.07 (s, 1H), 8.74 (dd, J=1.5, 4.5Hz, 1H), 8.70–8.66 (m, 1H), 7.65 (dd, J=2.4, 8.7 Hz, 1H), 7.56–7.52 (m,2H), 7.03 (d, J=8.4 Hz, 1H).

EXAMPLE 1064-(2-Chloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

a. 2-Chloro-5-hydroxyaniline: To a solution of 4-chloro-3-nitrophenol (1g, 5.76 mmol) in anhydrous ethanol (20 ml) was slowly added anhydroustin chloride (4.4 g, 23.2 mmol) at room temperature. The mixture wasrefluxed for 1 h. The mixture was cooled to room temperature and thenrotary evaporated to get an oily liquid. The liquid was basified withaqueous 2N NaOH (20 ml) to a final pH of 8. The resulting precipitatewas filtered and washed with water. The aqueous solution was extractedwith ethyl acetate (75 ml) and dried over anhydrous sodium sulfate. Theethyl acetate solution was rotary evaporated to dryness to give a palewhite solid (584 mg, 71%). ¹H NMR (CDCl₃): 7.07 (d, J=8.4 Hz, 1H), 6.27(d, J=3.0 Hz, 1H), 6.18 (dd, J=3.0, 9.0 Hz, 1H), 4.64 (s, 1H), 4.02 (bs,2H).

b.4-(2-Chloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine:A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol), 2-chloro-5-hydroxyaniline (42 mg, 0.290 mmol) and 2NHCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 48 h. Themixture was cooled to room temperature, neutralized with aqueous 2N NaOHto a pH of 6–7 and isolated as a yellow solid (6 mg, 8%). ¹H NMR(DMSO-d₆): 9.95 (s, 1H), 9.85 (s, 1H), 9.38–9.37 (m, 1H), 8.74–8.72 (m,1H), 8.55–8.52 (m, 1H), 7.59–7.54 (m, 1H), 7.37 (dd, J=0.6, 8.7 Hz, 1H),7.38 (s, 1H), 7.24 (s, 1H), 6.71 (dd, J=2.1, 8.7 Hz, 1H).

EXAMPLE 1074-(2-Chloro-5-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-chloro-5-hydroxyaniline (42 mg, 0.290 mmol) similar toExample 108 and isolated as a brown solid (3 mg, 4%). ¹H NMR (CDCl₃):8.68 (dd, J=1.8, 4.5 Hz, 2H), 8.13 (dd, J=1.8, 4.2 Hz, 2H), 7.99 (d,J=2.7 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.98 (s, 1H), 6.73(dd, J=2.7, 8.7 Hz, 1H).

EXAMPLE 108 4-(2,6-Dimethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243mmol), 2,6-dimethylaniline (45 μl, 0.365 mmol) and 2N HCl (150 μl) inwater:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooledto room temperature and basified with aqueous 2N NaOH to pH 10–12. Themixture was extracted with ethyl acetate (75 ml), which was washed withwater (2×20 ml), aqueous saturated NaCl (1×20 ml), and dried overanhydrous sodium sulfate. The ethyl acetate solution was rotaryevaporated to dryness and the residue was purified by columnchromatography to give a yellow oil (58 mg, 82%). ¹H NMR (CDCl₃):8.81–8.78 (m, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.83–7.77 (m, 1H), 7.36–7.30(m, 1H), 7.21–7.13 (m, 3H), 6.91 (s, 1H), 5.77 (s, 1H), 2.39 (s, 3H),2.23 (s, 6H).

EXAMPLE 109 4-(3-Methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine

A mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol),m-anisidine (16 μl, 0.140 mmol) and 2N HCl (75 μl) in water:ethanol(2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to roomtemperature and basified with aqueous 2N NaOH to pH 10–12. The resultingprecipitate was filtered, washed with water and aqueous ethanol to givea yellow solid (20 mg, 60%). ¹H NMR (CDCl₃): 8.87–8.85 (m, 1H),8.69–8.61 (m, 3H), 7.95 (s, 1H), 7.92–7.84 (m, 2H), 7.44–7.36 (m, 2H),7.33 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.05 (t, J=2.1 Hz, 1H), 6.98 (dd,J=2.1, 8.1 Hz, 1H), 6.79–6.75 (m, 1H), 3.86 (s, 3H).

EXAMPLE 110 4-(2,5-Dimethoxyanilino)-2,6-di(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and2,5-dimethoxyaniline (21 mg, 0.140 mmol) similar to Example 111 andisolated as a yellow oil (2 mg, 6%). ¹H NMR (CDCl₃): 8.86–8.84 (m, 1H),8.70–8.64 (m, 3H), 8.11 (s, 1H), 7.92 (s, 1H), 7.91–7.85 (m, 2H), 7.65(s, 1H), 7.43–7.36 (m, 2H), 6.87 (d, J=9.0 Hz, 1H), 6.61 (dd, J=3.0, 9.0Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).

EXAMPLE 111 4-(5-Methoxy-2-methylanilino)-2,6-di(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 andisolated as a white solid (21 mg, 61%). ¹H NMR (CDCl₃): 8.88–8.86 (m,1H), 8.71–8.60 (m, 3H), 7.92–7.83 (m, 2H), 7.62 (s, 1H), 7.44–7.34 (m,2H), 7.22 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.78(dd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 3H), 2.52 (s, 3H).

EXAMPLE 112 4-(2-Methoxy-5-methylanilino)-2,6-di(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and2-methoxy-5-methylaniline (19 mg, 0.140 mmol) similar to Example 111 andisolated as a yellow solid (12 mg, 35%). ¹H NMR (CDCl₃): 8.89–8.87 (m,1H), 8.69–8.64 (m, 3H), 7.92–7.84 (m, 3H), 7.89 (s, 1H), 7.55 (s, 1H),7.44–7.36 (m, 2H), 6.92 (dd, J=1.8, 8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),3.86 (s, 3H), 2.39 (s, 3H).

EXAMPLE 113 4-(2-Chloro-5-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and2-chloro-5-methoxyaniline (27 mg, 0.140 mmol) similar to Example 111 andisolated as a white solid (20 mg, 55%). ¹H NMR (CDCl₃): 8.87–8.82 (m,1H), 8.72–8.64 (m, 3H), 8.08 (d, J=2.7 Hz, 1H), 7.92 (s, 1H), 7.90–7.86(m, 2H), 7.45–7.38 (m, 3H), 7.33 (d, J=8.7 Hz, 1H), 6.67 (dd, J=3.0, 9.0Hz, 1H), 3.91 (s, 3H).

EXAMPLE 114 4-(2,5-Dimethylanilino)-2,6-di(2-pyridinyl)pyrimidine

The title compound was prepared from a mixture4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and2,5-dimethylaniline (17 μl, 0.140 mmol) similar to Example 111 andisolated as a yellow oil (7 mg, 21%). ¹H NMR (CDCl₃): 8.88–8.86 (m, 1H),8.71–8.68 (m, 1H), 8.64–8.58 (m, 2H), 7.92–7.82 (m, 2H), 7.50 (s, 1H),7.43–7.32 (m, 2H), 7.23 (s, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.09 (s, 1H),7.04 (dd, J=1.8, 7.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).

EXAMPLE 1154-(2,5-Dimethylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol), 2,5-dimethylaniline (36 μl, 0.290 mmol) and 2N HCl (150μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture wascooled to room temperature. The resulting precipitate was filtered,washed with water and aqueous ethanol to give a white solid (28 mg,42%). ¹H NMR (CDCl₃): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.27 (dd, J=1.5, 4.5Hz, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=1.8, 7.8 Hz,1H), 6.99 (s, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H).

EXAMPLE 1164-(2-Methoxy-5-methylamino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar toExample 115 and isolated as a white solid (48 mg, 69%). ¹H NMR (CDCl₃):8.79 (dd, J=1.8, 4.5 Hz, 2H), 8.30 (dd, J=1.8, 4.5 Hz, 2H), 7.97 (s,1H), 7.46 (s, 1H), 6.99 (dd, J=1.5, 8.1 Hz, 1H), 6.94 (s, 1H), 6.89 (d,J=8.4 Hz, 1H), 3.90 (s, 3H), 2.41 (s, 3H).

EXAMPLE 1174-(5-Hydroxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.193 mmol), 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) and 2NHCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. Themixture was cooled to room temperature and neutralized with aqueous 2NNaOH to pH 6–7. The mixture was extracted with ethyl acetate (75 ml),washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml) and driedover anhydrous sodium sulfate. The ethyl acetate solution was rotaryevaporated to dryness and the residue was purified by columnchromatography to give a yellow solid (18 mg, 27%). ¹H NMR (Acetone-d₆):9.53–9.51 (m, 1H), 8.85 (s, 1H), 8.71 (dd, J=1.8, 4.8 Hz, 1H), 8.67–8.63(m, 1H), 8.49 (s, 1H), 7.53–7.48 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=8.1Hz, 1H), 6.98 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 2.23 (s, 3H).

EXAMPLE 1184-(5-Hydroxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) similar toExample 117 and isolated as a tan solid (19 mg, 28%). ¹H NMR(Acetone-d₆): 8.91 (s, 1H), 8.75 (dd, J=1.2, 4.8 Hz, 2H), 8.55 (s, 1H),8.22 (dd, J=1.8, 4.8 Hz, 2H), 7.23 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.02(s, 1H), 6.76 (dd, J=3.0, 8.7 Hz, 1H), 2.23 (s, 3H).

EXAMPLE 1194-(5-Methoxy-2-piperidino-anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

-(4-Methoxy-2-aminophenyl)piperidine: To a solution of1-(4-methoxy-2-nitrophenyl)piperidine (238 mg, 1.01 mmol) in anhydrousethanol (20 ml) was slowly added anhydrous tin chloride (772 mg, 4.07mmol) at room temperature. The mixture was refluxed for 1 h. The mixturewas cooled to room temperature and then rotary evaporated to get an oilyliquid. The liquid was basified with aqueous 2N NaOH (20 ml) to a finalpH of 10. The resulting precipitate was filtered and washed with water.The aqueous solution was extracted with ethyl acetate (75 ml), washedwith water (2×20 ml) and dried over anhydrous sodium sulfate. The ethylacetate solution was rotary evaporated to give a dark brown liquid (153mg, 74%). ¹H NMR (CDCl₃): 6.90 (d, J=8.7 Hz, 1H), 6.29 (d, J=2.7 Hz,1H), 6.26 (dd, J=2.7, 8.1 Hz, 1H), 4.04 (bs, 2H), 3.69 (s, 3H), 2.75 (s,4H), 1.70–1.63 (m, 4H), 1.54 (s, 2H).

b.4-(5-Methoxy-2-piperidino-anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine:The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 1-(4-methoxy-2-aminophenyl)piperidine (60 mg, 0.290 mmol)similar to Example 117 and isolated as a green solid (1 mg, 1%). ¹H NMR(CDCl₃): 9.71–9.69 (m, 1H), 8.78–8.74 (m, 2H), 8.70 (s, 1H), 8.18 (s,1H), 7.46–7.41 (m, 1H), 7.16 (d, J=8.7 Hz, 1H), 6.90 (s, 1H), 6.66 (dd,J=2.7, 8.4 Hz, 1H), 3.90 (s, 3H), 2.83–2.79 (m, 4H), 1.81–1.74 (m, 4H),1.62 (s, 2H).

EXAMPLE 1204-(2-Cyano-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-cyano-5-methylaniline (38 mg, 0.290 mmol) similar to Example117 and isolated as a yellow solid (8 mg, 12%). ¹H NMR (CDCl₃):9.62–9.61 (m, 1H), 8.75–8.69 (m, 2H), 8.08 (s, 1H), 7.62 (s, 1H), 7.60(d, J=8.1 Hz, 1H), 7.46–7.41 (m, 1H), 7.12 (dd, J=0.9, 8.1 Hz, 1H), 7.00(s, 1H), 2.52 (s, 3H).

EXAMPLE 1214-(3,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3,5-dimethylaniline (36 μl, 0.290 mmol) similar to Example 117and isolated as a yellow solid (26 mg, 39%). ¹H NMR (CDCl₃): 9.66–9.64(m, 1H), 8.73 (s, 1H), 8.72–8.69 (m, 1H), 7.44–7.40 (m, 1H), 7.30 (s,1H), 7.04 (s, 2H), 6.93 (s, 1H), 6.90 (s, 1H), 2.38 (s, 3H), 2.37 (s,3H).

EXAMPLE 1224-(3,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3,5-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example117 and isolated as a yellow solid (29 mg, 38%). ¹H NMR (DMSO-d₆): 10.32(s, 1H), 9.48–9.46 (m, 1H), 8.76–8.74 (m, 1H), 8.62–8.58 (m, 1H),7.63–7.58 (m, 1H), 7.14 (s, 1H), 7.06 (s, 2H), 6.32 (s, 1H), 3.80 (s,6H).

EXAMPLE 1234-(2-Chloro-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-chloro-5-methylaniline (41 mg, 0.290 mmol) similar toExample 117 and isolated as a yellow solid (15 mg, 21%). ¹H NMR (CDCl₃):9.62–9.61 (m, 1H), 8.73–8.69 (m, 2H), 7.89 (s, 1H), 7.44–7.40 (m, 1H),7.37 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.00 (dd, J=0.9, 8.4 Hz, 1H), 6.88(s, 1H), 2.42 (s, 3H).

EXAMPLE 1244-(3-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-methoxy-5-trifluoromethylaniline (55 mg, 0.290 mmol) similarto Example 117 and isolated as a yellow solid (27 mg, 34%). ¹H NMR(CDCl₃): 9.65–9.64 (m, 1H), 8.75–8.70 (m, 2H), 7.46–7.41 (m, 2H), 7.36(s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H).

EXAMPLE 1254-(2-Chloro-5-methoxyanilino)-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine

4-Hydroxy-6-Trifluoromethyl-2-(6-trifluoromethyl-3-pyridinyl)pyrimidine:A mixture of 6-(trifluoromethyl)pyridine-3-amidine (1 g, 5.26 mmol) andethyl 4,4,4-trifluoro-2-butynoate (1.1 ml, 7.89 mmol) in ethanol (100ml) was stirred at 0° C. for 20 min. The temperature of the mixture wasraised to 60° C. and was let to stir at this temperature for 30 min.Then aqueous KOH (0.86 g in 20 ml water) was added dropwise. The mixturewas refluxed for 4 h. The mixture was cooled to room temperature, rotaryevaporated and isolated as a white solid (1.5 g, 94%). ¹H NMR (CDCl₃):9.72 (d, J=2.4 Hz, 1H), 8.87 (dd, J=2.1, 8.7 Hz, 1H), 7.93 (d, J=8.1 Hz,1H), 7.00 (s, 1H).

4-Chloro-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine:A mixture of4-hydroxy-6-trifluoromethyl-2-(6-trifluoromethyl-3-pyridinyl)-pyrimidine(145 mg, 0.469 mmol) and phosphorus oxychloride (10 ml) was refluxed for3 h. The mixture was cooled to room temperature and rotary evaporated toleave an oily residue. The residue was extracted with ethyl acetate (50ml), washed with water (2×20 ml) and dried over anhydrous sodiumsulfate. The ethyl acetate solution was concentrated in vacuo to give acrude solid (80 mg).

4-(2-Chloro-5-methoxyanilino)-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine:A mixture of crude4-chloro-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine(50 mg, 0.152 mmol), 2-chloro-5-methoxyaniline (50 mg, 0.229 mmol) and2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 120 h.The mixture was cooled to room temperature and basified with aqueous 2NNaOH to pH 10–12. The mixture was extracted with ethyl acetate (75 ml),washed with water (2×20 ml), with aqueous saturated NaCl (1×20 ml) anddried over anhydrous sodium sulfate. The ethyl acetate solution wasrotary evaporated to dryness and the residue was purified by preparativeTLC to give a white solid (3 mg, 4%). ¹H NMR (CDCl₃): 9.72 (s, 1H), 8.90(dd, J=3.0, 7.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (s, 1H), 7.40 (d,J=9.3 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H),3.86 (s, 3H).

EXAMPLE 1264-(5-Bromo-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

a. 5-Bromo-2-methoxyaniline: To a solution of 4-bromo-2-nitroanisole(500 mg, 2.15 mmol) in anhydrous ethanol (15 ml) was added slowlyanhydrous tin chloride (1.6 g, 8.62 mmol). The mixture was refluxed for1 h, then rotary evaporated to leave a brown oil which was neutralizedwith aqueous 2N NaOH (5 ml). The resulting solid was filtered and washedwith ethyl acetate. The aqueous and ethyl acetate solutions werecombined and washed with water. The ethyl acetate solution was rotaryevaporated to dryness and the residue was purified column chromatographyto give a white solid (46 mg, 11%). ¹H NMR (CDCl₃): 6.79 (dd, J=2.1, 9.0Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 6.61 (d, J=9.3 Hz, 1H), 3.84 (s, 2H),3.80 (s, 3H).

b.4-(5-Bromo-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine:The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-bromo-2-methoxyaniline (39 mg, 0.193 mmol) similar toExample 117 and isolated as a tan solid (26 mg, 32%). ¹H NMR (CDCl₃):9.67–9.66 (m, 1H), 8.77–8.71 (m, 3H), 7.55 (s, 1H), 7.48–7.43 (m, 1H),7.24 (dd, J=2.4, 8.7 Hz, 1H), 6.92 (s, 1H), 6.83 (d, J=9.0 Hz, 1H), 3.93(s, 3H).

EXAMPLE 1274-(2-Bromo-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

a. 2-Bromo-5-methoxyaniline: The title compound was prepared from4-bromo-3-nitroanisole (490 mg, 2.11 mmol), anhydrous ethanol (15 ml)and anhydrous tin chloride (1.6 g, 8.44 mmol) similar to Example 126aand isolated as a white solid (42 mg, 10%). ¹H NMR (CDCl₃): 7.26 (d,J=8.7 Hz, 1H), 6.31 (d, J=3.0 Hz, 1H), 6.22 (dd, J=2.7, 9.0 Hz, 1H),4.06 (s, 2H), 3.73 (s, 3H).

b.4-(2-Bromo-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine:The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-bromo-5-methoxyaniline (39 mg, 0.193 mmol) similar toExample 117 and isolated as a yellow solid (2 mg, 2%). ¹H NMR (CDCl₃):9.66 (s, 1H), 8.74–8.71 (m, 2H), 7.80 (s, 1H), 7.53 (d, J=9.0 Hz, 1H),7.48 (s, 1H), 7.45–7.41 (m, 1H), 6.93 (s, 1H), 6.69 (dd, J=3.0, 8.7 Hz,1H), 3.87 (s, 3H).

EXAMPLE 1284-[3-Methyl-5-(trifluoromethyl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 3-methyl-5-(trifluoromethyl)aniline (51 mg, 0.290 mmol)similar to Example 117 and isolated as a yellow solid (60 mg, 78%). ¹HNMR (DMSO-d₆): 10.60 (s, 1H), 9.45–9.44 (m, 1H), 8.77–8.75 (m, 1H),8.60–8.56 (m, 1H), 8.30 (s, 1H), 7.68 (s, 1H), 7.62–7.58 (m, 1H), 7.32(s, 1H), 7.16 (s, 1H), 2.45 (s, 3H).

EXAMPLE 1294-(5-Chloro-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-chloro-2-hydroxyaniline (42 mg, 0.290 mmol) similar toExample 117 and isolated as a tan solid (38 mg, 54%). ¹H NMR (DMSO-d₆):10.44 (s, 1H), 9.74 (s, 1H), 9.42 (s, 1H), 8.75–8.74 (m, 1H), 8.58–8.54(m, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 7.61–7.57 (m, 1H), 7.08 (dd, J=2.1,8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H).

EXAMPLE 1304-(4-Chloro-2,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar toExample 117 and isolated as a brown solid (52 mg, 63%). ¹H NMR (CDCl₃):9.66–9.64 (m, 1H), 8.76–8.71 (m, 2H), 8.35 (s, 1H), 7.54 (s, 1H),7.45–7.41 (m, 1H), 7.01 (s, 1H), 6.92 (s, 1H).

EXAMPLE 1314-(6-Chloro-3-methoxyanilino)-2-morpholino-6-(methyl)pyrimidine

The title compound was prepared from a mixture of4-(4-chloro-6-methyl-pyrimidin-2-yl)-morpholine (23 mg, 0.108 mmol) and6-chloro-m-anisidine (31 mg, 0.161 mmol) similar to Example 117 andisolated as a white solid (11 mg, 31%). ¹H NMR (CDCl₃): 8.27 (d, J=3.0Hz, 1H), 7.91 (s, 1H), 7.27 (d, J=9.0 Hz, 1H), 6.97 (s, 1H), 6.54 (dd,J=3.0, 8.7 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 8H), 2.14 (s, 3H).

EXAMPLE 1324-(2,4-Dichloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2,4-dichloro-5-methoxyaniline (44 mg, 0.232 mmol) similar toExample 117 and isolated as a brown solid (9 mg, 11%). ¹H NMR (CDCl₃):9.64–9.63 (m, 1H), 8.76–8.70 (m, 2H), 8.12 (s, 1H), 7.49 (s, 1H),7.46–7.41 (m, 2H), 6.95 (s, 1H), 4.00 (s, 3H).

EXAMPLE 1334-(Indol-4-ylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-aminoindole (38 mg, 0.290 mmol) similar to Example 117 andisolated as a tan solid (6 mg, 9%). ¹H NMR (CDCl₃): 9.75–9.74 (m, 1H),8.77–8.73 (m, 1H), 8.69 (dd, J=1.8, 5.1 Hz, 1H), 8.57 (s, 1H), 8.08 (s,1H), 7.44–7.38 (m, 2H), 7.31–7.23 (m, 3H), 6.85 (s, 1H), 6.50–6.48 (m,1H).

EXAMPLE 1344-(2-Acetyl-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-amino-4,5-dimethoxyacetophenone (56 mg, 0.290 mmol) similarto Example 117 and isolated as a tan solid (24 mg, 30%). ¹H NMR (CDCl₃):12.49 (s, 1H), 9.65–9.64 (m, 1H), 8.86 (s, 1H), 8.74–8.70 (m, 2H),7.45–7.41 (m, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 4.12 (s, 3H), 3.95 (s,3H), 2.68 (s, 3H).

EXAMPLE 1354-(2-Methyl-5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (1g, 3.90 mmol), 2-methyl-5-nitroaniline (890 mg, 5.90 mmol), and 2N HCl(3 ml) in water:ethanol (1:1, 200 ml) was refluxed for 48 h. The mixturewas cooled to room temperature and basified with aqueous 2N NaOH to pH10–12. The mixture was extracted with ethyl acetate (200 ml), washedwith water (2×100 ml), with aqueous saturated NaCl (1×100 ml) and driedover anhydrous sodium sulfate. The ethyl acetate solution was rotaryevaporated to dryness to give a tan solid (377 mg, 30%). ¹H NMR (CDCl₃):8.90 (s, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 2H), 8.30 (dd, J=1.5, 4.5 Hz,2H), 8.09 (dd, J 2.4, 8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.99 (s, 1H),6.87 (s, 1H), 2.47 (s, 3H).

EXAMPLE 1364-(5-Amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

To a solution of4-(2-methyl,5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(377 mg, 1.00 mmol) in anhydrous ethanol (20 ml) was added slowlyanhydrous tin chloride (758 mg, 4.00 mmol). The mixture was refluxed for1 h and then rotary evaporated to leave a brown oil. The brown oil wasbasified with aqueous 2N NaOH to give a final pH of 8. The resultingprecipitate was filtered and washed with ethyl acetate. The aqueousphase and organic phase was combined and washed with water (1×20 ml) anddried over anhydrous sodium sulfate. The ethyl acetate solution wasrotary evaporated to dryness to give a brown solid (212 mg, 57%). ¹H NMR(CDCl₃): 8.76 (dd, J=1.8, 4.8 Hz, 2H), 8.26 (dd, J=1.8, 4.8 Hz, 2H),7.11 (d, J=7.8 Hz, 1H), 7.12 (s, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.66 (s,1H), 6.63 (dd, J=2.4, 8.1 Hz, 1H), 3.72 (bs, 2H), 2.16 (s, 3H).

EXAMPLE 137N-[4-Methyl-3-(2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

A mixture of4-(5-amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride (25 mg, 0.067 mmol), benzoic acid (10 mg, 0.080 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.4 mg,0.080 mmol) in dichloromethane (5 ml) was stirred at room temperaturefor 24 h. The mixture was rotary evaporated to dryness and the residuewas purified by column chromatography to give a white solid (14 mg,47%). ¹H NMR (CDCl₃): 9.66 (s, 1H), 8.75–8.71 (m, 1H), 8.67 (bs, 1H),8.40 (s, 1H), 8.08 (dd, J=1.2, 8.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H),7.90–7.86 (m, 2H), 7.81 (s, 1H), 7.55–7.38 (m, 4H), 7.25 (d, J=8.4 Hz,1H), 6.71 (s, 1H), 2.23 (s, 3H).

EXAMPLE 1384-(2,5-Diethoxy-4-morpholinoanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2,5-diethoxy-4-morpholinoaniline dihydrochloride (98 mg, 0.290mmol) similar to Example 117 and isolated as a brown oil (3 mg, 3%). ¹HNMR (CDCl₃): 9.64–9.63 (m, 1H), 8.74–8.69 (m, 2H), 7.42–7.38 (m, 1H),7.33 (s, 1H), 6.83 (s, 1H), 6.60 (s, 1H), 4.13 (q, J=7.2 Hz, 4H),3.92–3.89 (m, 4H), 3.14–3.11 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).

EXAMPLE 1394-Methyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

A mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(20 mg, 0.058 mmol) and p-toluoyl chloride in pyridine (5 ml) wasstirred at room temperature for 15 h. Then water was added to themixture. The resulting precipitate was filtered, washed with excesswater and dried to give a tan solid (26 mg, 94%). ¹H NMR (CDCl₃): 8.77(dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.8, 4.5 Hz, 2H), 8.00 (s, 1H),7.83 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 7.34(s, 1H), 7.31 (d, J=7.5 Hz, 2H), 7.01 (s, 1H), 6.73 (s, 1H), 2.44 (s,3H), 2.29 (s, 3H).

EXAMPLE 140N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(20 mg, 0.058 mmol) and nicotinoyl chloride hydrochloride (10 mg, 0.058mmol) similar to Example 139 and isolated as a tan solid (13 mg, 47%).¹H NMR (DMSO-d₆): 10.50 (s, 1H), 9.85 (s, 1H), 9.12 (d, J=1.5 Hz, 1H),8.77 (dd, J=1.5, 4.5 Hz, 1H), 8.72 (d, J=5.7 Hz, 2H), 8.34–8.28 (m, 1H),8.21 (bs, 1H), 8.16 (d, J=6.0 Hz, 2H), 7.60–7.53 (m, 2H), 7.34 (d, J=8.1Hz, 1H), 7.14 (s, 1H), 2.25 (s, 3H).

EXAMPLE 1416-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(20 mg, 0.058 mmol) and 6-chloronicotinyl chloride (10 mg, 0.058 mmol)similar to Example 139 and isolated as a white solid (14 mg, 50%). ¹HNMR (CDCl₃): 8.88–8.87 (m, 1H), 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd,J=1.8, 4.5 Hz, 2H), 8.19 (dd, J=2.4, 8.4 Hz, 1H), 8.00 (s, 1H), 7.87 (s,1H), 7.49 (dd, J=0.9, 8.4 Hz, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.01 (s,1H), 6.76 (s, 1H), 2.32 (s, 3H).

EXAMPLE 142N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]-4-morpholino-benzamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(10 mg, 0.029 mmol) and 4-morpholinobenzoic acid (7 mg, 0.035 mmol)similar to Example 136 and isolated as a white solid (4 mg, 26%). ¹H NMR(CDCl₃): 8.76 (dd, J=1.8, 4.2 Hz, 2H), 8.29 (dd, J=1.8, 4.2 Hz, 2H),7.99 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.37 (dd, J=1.8, 8.1Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=9.0 Hz, 2H),6.73 (s, 1H), 3.89–3.86 (m, 4H), 3.31–3.28 (m, 4H), 2.28 (s, 3H).

EXAMPLE 1434-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(10 mg, 0.029 mmol) and 4-chlorobenzoyl chloride (6 mg, 0.035 mmol)similar to Example 139 and isolated as a white solid (7 mg, 50%). ¹H NMR(CDCl₃): 8.77 (d, J=6.0 Hz, 2H), 8.29 (d, J=6.0 Hz, 2H), 8.00 (s, 1H),7.83 (d, J=8.7 Hz, 2H), 7.81 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35 (s,2H), 7.01 (s, 1H), 6.75 (s, 1H), 2.30 (2, 3H).

EXAMPLE 1444-Methoxy-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(10 mg, 0.029 mmol) and p-anisoyl chloride (6 mg, 0.035 mmol) similar toExample 139 and isolated as a tan solid (10 mg, 71%). ¹H NMR (CDCl₃):8.77 (dd, J=1.5, 4.8 Hz, 2H), 8.29 (dd, J=1.5, 4.8 Hz, 2H), 7.99 (s,1H), 7.86 (d, J=8.7 Hz, 2H), 7.79 (s, 1H), 7.36 (dd, J=1.8, 8.4 Hz, 1H),7.32 (d, J=8.7 Hz, 2H), 7.02 (s, 1H), 6.99 (d, J=8.7 Hz, 2H), 3.88 (s,3H), 2.29 (s, 3H).

EXAMPLE 1454-Chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

The title compound was prepared from a mixture of4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(80 mg, 0.232 mmol) and 4-chloromethylbenzoyl chloride (53 mg, 0.278mmol) similar to Example 139 and isolated as a yellow solid (55 mg,48%). ¹H NMR (CDCl₃): 8.75 (dd, J=1.8, 4.8 Hz, 2H), 8.29 (dd, J=1.8, 4.8Hz, 2H), 8.02 (s, 1H), 7.96 (s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.51 (d,J=8.4 Hz, 2H), 7.37 (dd, J=1.8, 7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H),7.12 (s, 1H), 6.75 (s, 1H), 4.63 (s, 2H), 2.28 (s, 3H).

EXAMPLE 1464-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide

To a stirring mixture of4-chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide(48 mg, 0.096 mmol) and 1-methylpiperazine (16 pl, 0.0.144 mmol) inanhydrous tetrahydrofuran (5 ml) was added N,N-diisopropylethylamine(200 μl). The mixture was refluxed for 20 h. The mixture was cooled toroom temperature and then rotary evaporated to dryness. The residue waspurified by column chromatography and isolated as a tan solid (22 mg,41%). ¹H NMR (CDCl₃): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.5, 4.5Hz, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.47 (d,J=1.8 Hz, 2H), 7.37 (dd, J=1.5, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H),7.04 (s, 1H), 6.74 (s, 1H), 3.57 (s, 2H), 2.47 (s, 8H), 2.29 (s, 6H).

EXAMPLE 1474-(2,5-Dimethyl-4-hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-amino-2,5-dimethylphenol (40 mg, 0.290 mmol) similar toExample 117 and isolated as an orange solid (35 mg, 47%). ¹H NMR(CDCl₃): 8.79–8.77 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.14 (bs, 1H),7.91–7.86 (m, 1H), 7.46–7.42 (m, 1H), 7.09 (bs, 1H), 6.92 (s, 1H), 6.83(s, 1H), 6.46 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H).

EXAMPLE 1484-(2,5-Dimethyl-4-hydroxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol)and 4-amino-2,5-dimethylphenol (39 mg, 0.287 mmol) similar to Example117 and isolated as an orange solid (35 mg, 47%). ¹H NMR (CDCl₃): 9.75(d, J=1.2 Hz, 1H), 8.79–8.78 (m, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.20 (s,1H), 7.01 (s, 1H), 6.78 (s, 1H), 6.52 (s, 1H), 5.43 (s, 1H), 2.25 (s,3H), 2.16 (s, 3H).

EXAMPLE 1494-(2,5-Dimethyl-4-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-amino-2,5-dimethylphenol (40 mg, 0.290 mmol) similar toExample 117 and isolated as a white solid (2 mg). ¹H NMR (CDCl₃): 8.77(d, J=6.0 Hz, 2H), 8.27 (d, J=6.3 Hz, 2H), 7.05 (s, 1H), 6.86 (s, 1H),6.77 (s, 1H), 6.47 (s, 1H), 5.25 (bs, 1H), 2.26 (s, 3H), 2.19 (s, 3H).

EXAMPLE 1504-(4-Chloro-2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar toExample 117 and isolated as a brown solid (58 mg, 73%). ¹H NMR (CDCl₃):8.84–8.82 (m, 1H), 8.61–8.57 (m, 1H), 7.93–7.87 (m, 1H), 8.50 (bs, 1H),7.66 (s, 1H), 7.49–7.45 (m, 1H), 7.02 (s, 1H), 7.01 (s, 1H), 4.07 (s,3H), 3.92 (s, 3H).

EXAMPLE 1514-(4-Chloro-2,5-dimethoxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol)and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.287 mmol) similar to Example117 and isolated as a yellow solid (67 mg, 85%). ¹H NMR (CDCl₃): 9.77(d, J=1.5 Hz, 1H), 8.79–8.78 (m, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.50 (bs,1H), 7.70 (s, 1H), 7.05 (s, 1H), 7.04 (s, 1H), 4.06 (s, 3H), 3.93 (s,3H).

EXAMPLE 1524-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar toExample 117 and isolated as a yellow solid (64 mg, 79%). ¹H NMR (CDCl₃):8.82–8.80 (m, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.88–7.82 (m, 1H), 7.51 (s,1H), 7.43–7.38 (m, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 3.92(s, 3H), 3.84 (s, 3H), 2.19 (s, 3H).

EXAMPLE 1534-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol)and 4,5-dimethoxy-2-methylaniline (48 mg, 0.287 mmol) similar to Example117 and isolated as a brown solid (47 mg, 56%). ¹H NMR (CDCl₃): 9.74 (d,J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 2.4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H),7.51 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 3.93 (s, 3H),3.86 (s, 3H), 2.21 (s, 3H).

EXAMPLE 1544-(4,5-Dimethoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar toExample 117 and isolated as a brown solid (23 mg, 30%). ¹H NMR (CDCl₃):9.54 (dd, J=1.5, 4.5 Hz, 2H), 9.05 (dd, J=1.5, 4.5 Hz, 2H), 7.98 (s,1H), 7.60 (s, 2H), 7.29 (s, 1H), 4.71 (s, 3H), 4.63 (s, 3H), 3.00 (s,3H).

EXAMPLE 155 4-(2-Chloro-5-methoxyanilino)-6-methyl-2-aminopyrimidine

The title compound was prepared from a mixture of2-amino-4-chloro-6-methyl-pyrimidine (100 mg, 0.696 mmol) and2-chloro-5-methoxyaniline hydrochloride (203 mg, 1.05 mmol) similar toExample 117 and isolated as a white solid (132 mg, 72%). ¹H NMR (CDCl₃):7.77 (d, J=2.7 Hz, 1H), 7.28 (d, J=9.0 Hz, 6.74 (s, 1H), 6.57 (dd,J=3.0, 8.7 Hz, 1H), 6.04 (s, 1H), 4.81 (s, 2H), 3.82 (s, 3H), 2.26 (s,3H).

EXAMPLE 1564-(3-Trifluoromethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25mg, 0.096 mmol), 3-trifluoromethoxyaniline (19 μl, 0.144 mmol), and 2NHCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. Themixture was cooled to room temperature and the resulting precipitate wasfiltered, washed with water, water:ethanol (2:1) and dried to give ayellow solid (23 mg, 59%). ¹H NMR (CDCl₃): 8.88–8.85 (m, 1H), 8.59–8.55(m, 1H), 7.93–7.87 (m, 1H), 7.59 (s, 1H), 7.48 (t, J=8.3 Hz, 1H), 7.45(dd, J=1.2, 7.5 Hz, 1H), 7.36 (s, 1H), 7.30–7.29 (m, 1H), 7.16–7.10 (m,1H), 7.05 (s, 1H).

EXAMPLE 1574-(4,5-Dimethoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar toExample 117 and isolated as a red solid (8 mg, 11%). ¹H NMR (CDCl₃):9.69 (s, 1H), 8.74–8.68 (m, 2H), 7.56 (s, 1H), 7.43–7.39 (m, 1H), 6.84(s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.23(s, 3H).

EXAMPLE 1584-(4-Chloro-2,5-dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride

The title compound was prepared from a mixture of4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar toExample 117 and isolated as a brown solid (55 mg, 68%). ¹H NMR (CDCl₃):8.78 (dd, J=1.8, 4.8 Hz, 2H), 8.31 (dd, J=1.8, 4.8 Hz, 2H), 8.24 (s,1H), 7.52 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 3.98 (s, 3H), 3.91 (s,3H).

EXAMPLE 1594-(2-Hydroxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 2-hydroxy-5-methylaniline (36 mg, 0.290 mmol) similar toExample 117 and isolated as a brown solid (10 mg, 15%). ¹H NMR(Acetone-d₆): 9.58 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.72–8.68 (m,2H), 7.89 (s, 1H), 7.58–7.53 (m, 1H), 7.24 (s, 1H), 6.92 (s, 2H), 2.33(s, 3H).

EXAMPLE 1604-(N-Methyl-3-methoxyanilino)-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine

A mixture of 4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (180mg, 0.693 mmol) and N-methyl-3-methoxyaniline (112 mg, 0.816 mmol) in 3mL of solvent (ethanol:water=2:1) was refluxed for 20 h. The solvent wasremoved under reduced pressure and the residue was dissolved in 25 mL ofethyl acetate. The ethyl acetate solution was washed with 25 mL of 1MNaOH, and the aqueous layer was reextracted with ethyl acetate (25 mL).The combined organic extracts were washed with saturated NaCl and driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby flash column chromatography (40–45% ethyl acetate/hexanes) to givethe title compound as an oil (250 mg, 0.693 mmol, 100%). ¹H NMR (CDCl₃):8.86 (dd, J=0.6, 4.5 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 7.85 (dt, J=1.8,7.8 Hz, 1H), 7.42 (m, 2H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 6.86 (m, 1H),6.82 (m. 1H), 3.85 (s, 3H), 3.68 (s, 3H).

EXAMPLE 1614-(3,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine (150 mg, 0.578mmol) and 3,5-dimethoxyaniline (95 mg, 0.621 mmol) similar to Example160 and was isolated as off-white solid (119 mg, 0.316 mmol, 55%). ¹HNMR (DMSO-d₆): 10.31 (s, br, 1H), 8.80 (m, 2H), 8.17 (m, 2H), 7.17 (s,1H), 7.04 (s, 2H), 6.32 (m, 1H), 3.80 (s, 6H), 3.53 (s, 1H).

EXAMPLE 1624-(5-Chloro-2-methoxyanilino)-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine (150 mg, 0.578mmol) and 5-chloro-2-methoxyaniline (98 mg, 0.621 mmol) similar toExample 160 and was isolated as off-white solid (84 mg, 0.221 mmol,38%). ¹H NMR (CDCl₃/MeOH-d₄): 8.72 (d, J=4.2 Hz, 2H), 8.51 (s, 1H), 8.34(d, J=4.5 Hz), 7.09 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 3.93 (s, 3H)

EXAMPLE 1634-(3,5-Dimethoxyanilino)-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine

a. 4-Chloro-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine. Amixture of POCl₃ (freshly distilled, 0.50 mL, 5.35 mmol) in 2.5 mL ofDMF was stirred at 0° C. for 45 min. To the mixture was added2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-4-pyrimidinol (98 mg,0.317 mmol) in 0.5 mL of DMF and the mixture was allowed to warm to roomtemperature. The resulting mixture was heated overnight at 100° C. Thereaction mixture was cooled to room temperature and it was extractedwith ethyl acetate (10 mL×3). The combined extracts were washed withwater (10 mL×3) and saturated NaCl, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography(5% ethyl acetate/hexanes) to obtain the title compound as a white solid(74 mg, 0.226 mmol, 72%, mp 109–110° C.). ¹H NMR (CDCl₃): 8.30 (s, 2H),7.51 (s, 1H).

b.4-(3,5-Dimethoxyanilino)-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine.The title compound was prepared from4-chloro-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine (57mg, 0.174 mmol) and 3,5-dimethoxyaniline (38 mg, 0.248 mmol) similar toExample 160 and was isolated as a yellow crystalline solid (58 mg, 0.130mmol, 75%). ¹H NMR (CDCl₃): 8.25 (s, 2H), 7.25 (s, br, 1H), 7.02 (s,1H), 6.62 (m, 2H), 6.38 (t, J=1.8 Hz, 1H), 3.84 (s, 6H).

EXAMPLE 1644-(2-Chloro-5-methoxyanilino)-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine (52mg, 0.159 mmol) and 2-chloro-5-methoxyaniline (40 mg, 0.255 mmol)similar to Example 160 and was isolated as a yellow crystalline solid(13 mg, 0.029 mmol, 18%). ¹H NMR (CDCl₃): 8.27 (s, 2H), 7.76 (s, br,1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.02 (s, 1H), 6.77 (m, 1H), 3.90 (s,3H).

EXAMPLE 1654-(2-Methoxy-5-methyl-4-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (51 mg, 0.194mmol) and 2-methoxy-5-methyl-4-nitroaniline (43 mg, 0.236 mmol) similarto Example 160 and was isolated as off-white crystalline solid (mp128–133° C., 23 mg, 0.057 mmol, 29%). ¹H NMR (CDCl₃/MeOH-d4): 9.42 (s,1H), 8.75 (m, 1H), 8.62 (m, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.42 (dd,J=4.8, 8.1 Hz, 1H), 6.82 (s, 1H), 4.01 (s, 3H), 2.01 (s, 3H).

EXAMPLE 1664-(1H-5-Indolyl-amino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (42mg, 0.162 mmol), 1H-5-indolylamine (31 mg, 235 mmol) and potassiumcarbonate (25 mg, 0.180 mmol) was heated overnight in 1 mL of DMF at100° C. in a sealed tube. The reaction mixture was cooled to roomtemperature, diluted with 20 mL of ethyl acetate, washed with water (20mL×3) and saturated NaCl. The organic layer was dried over Na₂SO₄,filtered, concentrated and the residue was purified by flash columnchromatography (30% ethyl acetate/hexanes) to obtain the title compoundas a white solid (mp 142–143° C., 45 mg, 0.127 mmol, 78%). ¹H NMR(CDCl₃): 9.56 (d, J=1.5 Hz, 1H), 8.74 (dt, J=1.8, 8.1 Hz, 1H), 8.63 (dd,J=3, 5.1 Hz, 1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.30 (d, J=3 Hz, 1H), 7.19(m, 1H), 6.82 (s, 1H), 6.55 (d, J=3 Hz, 1H).

EXAMPLE 1674-(5-Methoxy-2-methyl-4-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (48 mg, 0.185mmol) and 5-methoxy-2-methyl-4-nitroaniline (35 mg, 0.192 mmol) similarto Example 166 and was isolated as a white solid (mp 128–132° C., 11 mg,0.027 mmol, 15%). ¹H NMR (CDCl₃): 9.62 (s, 1H), 8.68 (m, 2H), 7.79 (s,1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.01 (s, 1H), 4.02 (s, 3H), 2.63 (s,1H).

EXAMPLE 1684-(3-Trifluoromethyl-1-pyrazolyl)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285mmol) and 3-trifluromethyl-pyrazol (48 mg, 0.353 mmol) similar toExample 166 and was isolated as a white solid (mp 139–140° C., 53 mg,0.148 mmol, 52%). ¹H NMR (CDCl₃): 9.73 (s, 1H), 8.82 (m, 3H), 8.26 (s,1H), 7.50 (m, 1H), 6.87 (d, J=2.7 Hz, 1H).

EXAMPLE 1694-(4,5-Dihydro-2-thiazolyl-amino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289mmol) and 2-amino-2-thiazoline (37 mg, 0.362 mmol) similar to Example166 and was isolated as a white solid (20 mg, 0.61 mmol, 21%). ¹H NMR(CDCl₃/MeOH-d₄) 9.45 (s, 1H), 8.73 (dt, 1.8, 8.1 Hz, 1H), 8.58 (dd,J=1.8, 5.1 Hz, 1H), 7.47 (m, 1H), 6.70 (s, 1H), 3.93 (t, J=6.6 Hz, 2H),3.04 (t, J=7.2 Hz, 2H).

EXAMPLE 170 4-(1-Pyrazolyl)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285mmol) and pyrazole (28 mg, 0.425 mmol) similar to Example 166 and wasisolated as a white solid (mp 151–152° C., 67 mg, 0.230 mmol, 81%). ¹HNMR (CDCl₃) 9.71 (s, 1H), 8.77 (m, 3H), 8.19 (s, 1H), 7.88 (m, 1H), 7.47(m, 1H), 6.61 (dd, J=1.5, 2.7 Hz, 1H).

EXAMPLE 1714-(4,5,6,7-Tetrahydro-1H-indazolyl)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (76 mg, 0.293mmol) and 4,5,6,7-tetrahydroindazole (44 mg, 0.360 mmol) similar toExample 166 and was isolated as a white solid (25 mg, 0.072 mmol, 25%%). ¹H NMR (CDCl₃) 9.68 (d, J=1.2 Hz, 1H), 8.75 (m, 2H), 8.40 (s, 1H),8.07 (s, 1H), 7.45 (ddd, J=1.2, 5.1, 9.0 Hz, 1H), 2.73 (m, 4H), 1.88 (m,4H).

EXAMPLE 1724-(1H-3-Pyrazolyl-amino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289mmol) and 3-amino pyrazole (31 mg, 0.373 mmol) similar to Example 166and was isolated as a white solid (mp 230° C. decompose, 31 mg, 0.101mmol, 35%). ¹H NMR (DMSO-d₆) 9.62 (d, J=1.2 Hz, 1H), 8.77 (m, 3H), 7.71(s, 1H), 7.62 (dd, J=4.5, 7.5 Hz, 1H), 6.09 (d, J=3 Hz, 1H), 5.89 (s,1H).

EXAMPLE 1736-Methyl-2-(2-pyridinyl)-4-(3-trifloromethylbenzylamino)-pyrimidine

A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4mmol), 3-trifluoromethylbenzylamine (70.1 mg, 0.4 mmol), water (5 ml)and 2N HCl (300 μl) was refluxed for two days. The resulting solutionwas basified to pH ˜11 with ammonia and extracted with ethyl acetate (10ml×3). The combined ethyl acetate extracts were dried with sodiumsulfate, and evaporated under vacuum. The residue was purified by columnchromatography (hexane/ethyl acetate: 1/1) to give the title compound asa solid (34 mg, 25%). ¹H NMR (CD₃OD): 8.59 (d, J=4.2 Hz, 1H), 8.27 (m,2H), 7.86 (m, 2H), 7.43 (m, 2H), 6.18 (s, 2H), 4.76 (s, 2H), 2.26 (s,3H).

EXAMPLE 174 6-Methyl-4-(3-phenoxyanilino)-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and3-phenoxyaniline (74.0 mg, 0.4 mmol) similar to Example 173 and wasisolated as a white solid. (96 mg, 68%). ¹H NMR (CDCl₃): 8.62 (d, J=4.2Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.21 (m, 5H),6.94 (m, 5H), 6.64 (d, J=8.1 Hz, 1H), 6.49 (s, 1H), 2.33 (s, 3H),

EXAMPLE 175 4-(3-Chloroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and3-chloroaniline (50.8 mg, 0.4 mmol) similar to Example 173 and wasisolated as a white solid (99 mg, 84%). ¹H NMR (CDCl₃): 8.59 (d, J=4.2Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.80 (br, 1H), 7.67 (t, J=1.5 Hz, 1H),7.38 (s, 1H), 7.19 (m, 1H), 7.10 (m, 2H), 6.91 (m, 1H), 6.41 (s, 1H),2.28 (s, 3H).

EXAMPLE 176 4-(3,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and3,4-dimethoxyaniline (61.2 mg, 0.4 mmol) similar to Example 173 and wasisolated as a white solid (108 mg, 84%). ¹H NMR (CDCl₃): 8.63 (d, J=4.2Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.18 (m, 2H),6.7 (s, 1H), 6.71 (s, 2H), 6.28 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H),2.29 (s, 3H).

EXAMPLE 1774-(4-Fluoro-3-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and4-fluoro-3-methoxyaniline (56.4 mg, 0.4 mmol) similar to Example 173 andwas isolated as a white solid (96.7 mg, 78%). ¹H NMR (CDCl₃): 8.63 (d,J=4.2 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.42 (s,1H), 7.20 (m, 1H), 7.0 (d, J=7.5 Hz, 1H), 6.90 (m, 1H), 6.69 (m, 1H),3.71 (s, 3H), 2.30 (s, 3H),

EXAMPLE 178 4-(3-Isopropoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine

The title compound was prepared from4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and3-isopropoxyaniline (60.4 mg, 0.4 mmol) similar to Example 173 and wasisolated as a white solid (88 mg, 69%). ¹H NMR (CDCl₃): 8.64 (d, J=4.2Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.7 (t, J=8.1 Hz, 1H), 7.24 (m, 1H),7.15 (m, 1H), 6.96 (s, 1H), 6.76 (m, 2H), 6.60 (d, J=8.1 Hz, 1H), 6.18(m, 1H), 4.45 (m, 1H), 2.37 (s, 3H), 1.25 (d, J=6.0 Hz, 6H).

EXAMPLE 1794-(3,4-Dimethoxyanilino)-6-trifluoromethyl-2-(2-pyridinyl)pyrimidine

a. 4-Hydroxy-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine. To a solutionof pyridine-2-carboxamidine hydrochloride (5.0 g, 33.2 mmol) in 20 ml ofwater was added concentrated aqueous KOH and the resulting mixture wasextracted with ethyl acetate (50 mL×3). The extract was evaporated undervacuum to afford 4.0 g of free base. To a solution of the free base and4,4,4-trifluoro-but-2-ynoic acid ethyl ester (6.0 g, 36 mmol) in ethanol(50 mL) at 0° C.˜60° C. was added dropwise potassium hydroxide solution(1.68 g in 40 mL water) in twenty minutes. The solution was thenrefluxed 2.5 h. The solvent was evaporated under vacuum and the residuewas extracted with ethyl acetate (30 ml×3). The combined ethyl acetateextracts were dried with sodium sulfate, evaporated to give a solid. Itwas recrystallized with Hexane/methylene chloride/methanol: 6/2/1) togive the product as a white solid (2.50 g, 31.2%). ¹H NMR (CD₃OD): 8.63(d, J=4.8 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.49(m, 1H), 6.73 (s, 1H), 4.76 (s, 1H).

b. 4-Chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine. A mixture of4-hydroxy-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (2.50 g, 10.37mmol) and phosphorus oxychloride (20 mL) was refluxed for 3 h. Theresulting solution was evaporated under vacuum and the residue wasbasified to pH ˜11 with ammonia and extracted with ethyl acetate (15ml×3). The combined ethyl acetate extracts were dried with sodiumsulfate, evaporated to give a solid. The solid was purified by columnchromatography (hexane/ethyl acetate: 2/1˜1/3) to afford a yellow solid(2.30 g, 86%). ¹H NMR (CDCl₃): 8.76 (d, J=2.7 Hz, 1H), 8.42 (d, J=7.8Hz, 1H), 7.76 (t, J=1.8 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.34 (t, J=5.1Hz, 1H).

c. 4-(3,4-Dimethoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine.The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (51.8 mg, 0.2mmol) and 3,4-dimethoxyaniline (51.8 mg, 0.2 mmol) similar to Example173 and was isolated as a white solid (61 mg, 81%). ¹H NMR (CDCl₃): 8.71(d, J=0.9 Hz, 1H), 8.43 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.50(S, 1H), 7.35 (m, 1H), 6.77 (m, 4H), 3.80 (s, 3H), 3.77 (s, 3H).

EXAMPLE 1804-(5-Chloro-2-methoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (100mg, 0.385 mmol), 2-methoxy-5-chloroaniline (90 mg, 0.577 mmol) and 2NHCl (150 μl) in 1:1 ethanol/water (5 ml) was refluxed for 48 h. Theresulting yellow solid was collected by filtration, washed with water,ethanol/water (1:4) and then dried under vacuum to give the titlecompound (100 mg, 67%). ¹H NMR (CDCl₃): 9.66 (d, J=1.8 Hz, 1H),8.70–8.76 (m, 2H), 7.68 (dd, J=7.5, 1.0 Hz, 1H), 7.44 (dd, J=7.5, 1.0Hz, 1H), 7.09 (dd, J=8.7, 2.7 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J=8.7 Hz,1H), 3.91 (s, 3H).

EXAMPLE 1814-(2-Methoxy-5-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol)and 2-methoxy-5-nitroaniline (39 mg, 0.230 mmol), similar to Example 180and was isolated as a yellow solid (30 mg, 51%). ¹H NMR (CDCl₃): 9.760(d, J=1.5 Hz, 1H), 8.86 (dd, J=1.8, 2.7 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H),8.10 (dd, J=2.7, 9.0 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.08(s, 3H).

EXAMPLE 1824-(5-Methoxy-2-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol)and 5-methoxy-2-nitroaniline (39 mg, 0.230 mmol), similar to Example 180and was isolated as an off white solid (35 mg, 58%). ¹H NMR (CDCl₃):9.69 (d, J=1.5 Hz, 1H), 8.83 (dd, J=1.5, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz,1H), 8.08 (d, J=9.6 Hz, 1H), 7.11 (s, 1H), 6.27 (dd, J=2.7, 9.6 Hz, 1H),6.15 (d, J=2.7 Hz, 1H), 3.83 (s, 3H).

EXAMPLE 1834-(3,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol)and 3,5-dimethoxyaniline (35 mg, 0.23 mmol), similar to Example 180 andwas isolated as a pale solid (30 mg, 52%). ¹H NMR (CDCl₃): 9.74 (d,J=1.5 Hz, 1H), 7.78 (m, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.10(s, 1H), 6.53 (d, J=2.1 Hz, 2H) 6.39 (t, J=2.1 Hz, 1H), 3.83 (s, 6H).

EXAMPLE 1844-(5-Carboxy-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 5-carboxy-2-methoxyaniline (38 mg, 0.231 mmol), similar to Example180 and was isolated as an off white solid (20 mg, 33%). ¹H NMR (CDCl₃):9.99 (brs, 1H), 9.660 (d, J=1.5 Hz, 1H), 8.86 (m, 3H), 7.80 (d, 2H), 7.2(m, 2H), 3.94 (s, 3H).

EXAMPLE 1854-(5-Hydroxy-2-nitroanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol)and 5-hydroxy-2-nitroaniline (52 mg, 0.34 mmol) similar to Example 180.The reaction mixture was neutralized with 2N NaOH to pH 7.0 and thesolvent was removed under vacuo. The product was purified by columnchromatography (20% ethyl acetate in hexane) to give 55 mg (63%) of thetitle compound as a light yellow solid. ¹H NMR (CDCl₃): 9.40 (d, J=1.2Hz, 1H), 8.71 (dd, J=1.2, 4.8 Hz, 1H), 8.57 (ddd, J=2.1, 3.9, 7.8 Hz,1H), 8.04 (d, J=2.7 Hz, 1H), 7.42 (dd, J=3.9, 8.7 Hz, 1H), 7.32 (dd,J=6.0, 9.0 Hz, 1H), 7.23 (s, 1H), 6.92 (d, J=9.0 Hz, 1H), 6.19 (s, 2H).

EXAMPLE 1864-(2-Ethylsulfonyl-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar toExample 180. The reaction mixture was evaporated under vacuum to give aresidue. The residue was precipitated using acetone to give the productas a yellow solid (30 mg, 46%). ¹H NMR (DMSO-d₆): 9.45 (s, 1H), 8.71 (m,3H), 7.84 (brs, 1H), 7.0 (brd, 1H), 6.08 (brd, 1H), 3.0 (q, 2H), 1.0 (t,3H).

EXAMPLE 1874-(2-Methoxy-5-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.152 mmol)and 2-methoxy-5-methylaniline (28 mg, 0.231 mmol) similar to example 180and was isolated as a solid (43 mg, 81%). ¹H NMR (CDCl₃): 9.73 (m, 1H),8.44–8.41 (m, 1H), 7.81–7.75 (m, 1H), 7.46 (s, 1H), 7.34–7.28 (m, 2H),7.23 (t, J=8.1 Hz, 1H), 7.09–7.06 (m, 1H), 7.00–6.97 (m, 1H), 6.55 (d,J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).

EXAMPLE 1884-(5-Hydroxy-2-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 5-hydroxy-2-methylaniline (28 mg, 0.231 mmol) similar to example 185and was isolated as a pale solid (40 mg, 75%). ¹H NMR (CDCl₃): 9.73 (m,1H), 8.44–8.41 (m, 1H), 7.81–7.75 (m, 1H), 7.46 (s, 1H), 7.34–7.28 (m,2H), 7.23 (t, J=0.1 Hz, 1H), 7.09–7.06 (m, 1H), 7.00–6.97 (m, 1H), 6.55(d, J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).

EXAMPLE 1894-(2-Chloro-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2-chloro-5-hydroxyaniline (30 mg, 0.231 mmol) similar to Example 185and was isolated as an off white solid (15 mg, 28%). ¹H NMR (DMSO-d₆):9.89 (s, 1H), 9.85 (brs, NH), 8.74 (d, J=5.7, 1H), 8.22 (d, J=7.8 Hz,1H), 7.97 (ddd, J=1.8, 5.7, 7.8 Hz, 1H), 7.54 (ddd, J=4.5, 6.0, 7.8 Hz,1H), 7.35 (m, 2H), 7.19 (s, 1H), 6.70 (dd, J=2.7, 5.7 Hz, 1H).

EXAMPLE 1904-(2-Methoxy-5-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol)and 2-methoxy-5-methylaniline (46 mg, 0.34 mmol) similar to Example 180.After completion of the reaction the solvent was removed under reducedpressure. The product was purified (5 mg) by preparative TLC plate using1:1 hexane/ethyl acetate as mobile phase. ¹H NMR (DMSO-d₆): 9.68 (s,1H), 8.75 (d, J=3.6, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.00 (t, J=7.2 Hz,1H), 7.55 (dd, J=4.0, 7.2 Hz, 1H), 7.04 (m, 2H), 3.82 (s, 3H), 2.02 (s,3H).

EXAMPLE 1914-(2-Ethylsulfonyl-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar toExample 186 and was isolated as a yellow solid (35 mg, 54%). ¹H NMR(CDCl₃): 8.88 (s, 1H), 8.60 (brt, 2H), 8.01 (t, 1H), 7.52 (m, 2H), 7.01(m, 2H), 3.02 (q, 2H), 1.22 (t, 3H).

EXAMPLE 1924-(2-Hydroxy-5-isopropylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2-hydroxy-5-isopropylaniline (35 mg, 0.231 mmol) similar to Example185 and was isolated as a solid (32 mg, 55%). ¹H NMR (DMSO-d₆): 8.74 (s,1H), 8.73 (d, J=0.9 Hz, 1H), 8.35 (d, J=7.8 Hz, 2H), 7.95 (t, J=8.1 Hz,2H), 7.54 (m, 2H), 6.60 (m, 2H), 2.78 (sep, J=6.9 Hz, 1H), 1.20 (d,J=6.9 Hz, 6H).

EXAMPLE 1934-(5-Hydroxy-2-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 5-hydroxy-2-methylaniline (34 mg, 0.231 mmol) similar to Example 190and was isolated as a solid (3 mg). ¹H NMR (CDCl₃): 9.74 (d, J=1.2 Hz,1H), 8.76–8.71 (m, 2H), 7.30 (brs, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.87(brd, 1H), 6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.73 (s, 1H), 2.21 (s, 3H).

EXAMPLE 1944-(2-Chloro-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2-chloro-5-hydroxyaniline (33 mg, 0.231 mmol) similar to Example 190and was isolated as a solid (6 mg). ¹H NMR (CDCl₃): 9.72 (d, J=1.5 Hz,1H), 8.78 (dd, J=5.7, 1.5 Hz, 1H), 8.73 (d, J=1.2 Hz, 1H), 7.33 (d,J=8.7 Hz, 1H), 7.05 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.73 (dd, J=8.7,2.7 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.19 (dd, J=8.4, 2.7 Hz, 1H).

EXAMPLE 1954-(3,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol)and 3,5-dimethoxyaniline (26 mg, 0.172 mmol) similar to Example 180 andwas isolated as a light yellow solid (16 mg, 37% yield). ¹H NMR (CDCl₃):8.85 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d, J=6.9 Hz, 1H), 7.89 (ddd, J=9.3,7.5, 1.5 Hz, 1H), 7.65 (brs, 1H), 7.45 (dd, J=9.3, 4.5 Hz, 1H), 7.09 (s,1H), 6.51 (d, J=1.8 Hz, 1H), 6.37 (t, J=1.8 Hz, 1H), 3.93 (s, 6H).

EXAMPLE 1964-(2,5-Dimethylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared similar to4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol)and 2,5-dimethylaniline (21 mg, 0.172 mmol) similar to Example 180 andwas isolated as an off white solid (35 mg, 80% yield). ¹H NMR (CDCl₃):9.74 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 2.4 Hz, 1H), 8.71 (d, J=2.4 Hz,1H), 7.48 (brs, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.12 (m, 2H), 6.65 (s, 1H),2.36 (s, 3H), 2.23 (s, 3H).

EXAMPLE 1974-(5-Chloro-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol)and 5-chloro-2-methoxyaniline (27 mg, 0.173 mmol) similar to Example 185and was isolated as a solid (10 mg, 23% yield). ¹H NMR (CDCl₃): 9.72 (d,J=1.2 Hz, 1H), 8.82 (t, J=1.8 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.23(brs, 1H), 7.71 (brs, 1H), 7.15 (dd, J=8.4, 2.4 Hz, 1H), 7.04 (s, 1H),6.88 (d, J=8.4 Hz, 1H), 3.90 (s, 3H).

EXAMPLE 1984-(5-Chloro-2-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol)and 5-chloro-2-hydroxyaniline (25 mg, 0.173 mmol) similar to Example 185and was isolated as a solid (7 mg, 16% yield). ¹H NMR (CDCl₃): 9.68 (d,J=0.9 Hz, 1H), 8.84 (t, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.89(brs, 1H), 7.41 (s, 1H), 7.07 (m, 2H), 6.91 (d, J=8.7 Hz, 1H).

EXAMPLE 1994-(5-Hydroxy-2-isopropylanilino)-2-(2-pyrazinyl)-6-trifluoromethypyrimidine

The title compound was prepared from4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol)and 5-hydroxy-2-isopropylaniline (26 mg, 0.173 mmol) similar to Example190 and was isolated as a solid. ¹H NMR (CDCl₃): 9.75 (d, J=1.2 Hz, 1H),8.77 (t, J=1, 8 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 7.29 (brs, 1H), 7.27(s, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.70 (s,1H), 4.13 (sep, J=6.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).

EXAMPLE 2004-(2,5-Dimethoxyphenylethylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol)and 2,5-dimethoxyphenylethylamine (28 mg, 0.232 mmol) similar to Example186 and was isolated as an off white solid (35 mg, 54% yield). ¹H NMR(CDCl₃): 9.59 (brs, 1H), 8.69 (d, J=4.8 Hz, 1H), 7.37 (dd, J=4.8, 8.4Hz, 1H), 6.76 (m, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.00 (t, 2H), 1.67(s, 2H).

EXAMPLE 2014-(2,5-Dimethyl-4-hydroxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 2,5-dimethyl-4-hydroxyaniline (40 mg, 0.288 mmol) similar to Example190 and was isolated as a solid. ¹H NMR (CDCl₃): 9.51 (brs, 1H), 8.72(d, J=8.4 Hz, 1H), 8.63 (d, J=3.6 Hz, 1H), 7.45 (dd, J=7.5, 3.5 Hz, 1H),7.33 (s, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.45 (brs, 1H), 2.25 (s, 3H),2.16 (s, 3H).

EXAMPLE 2024-(3,4,5-Trichloroanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 3,4,5-trichloroaniline (56 mg, 0.288 mmol) similar to Example 180and was isolated as a white solid (30 mg, 37%). ¹H NMR (CDCl₃): 9.58 (d,J=1.5 Hz, 1H), 8.99 (ddd, J=8.4, 4.9, 1.5 Hz, 1H), 8.79 (dd, J=5.4, 1.5Hz, 1H), 7.99 (s, 1H), 7.76 (dd, J=7.8, 5.1 Hz, 1H), 7.40 (s, 1H).

EXAMPLE 2034-(2-Cyano-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 2-cyano-4,5-dimethoxyaniline (48 mg, 0.288 mmol) similar to Example185 and isolated as a solid (8 mg, 10%). ¹H NMR (CDCl₃): 9.62 (d, J=1.4Hz, 1H), 8.69 (m, 2H), 7.43 (dd, J=5.4, 1.5 Hz, 1H), 7.07 (s, 1H), 6.93(s, 1H), 6.70 (s, 1H).

EXAMPLE 2044-(3-Methoxy-dibenzofuran-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 4-amino-3-methoxydibenzofuran (61 mg, 0.288 mmol) similar to Example185 and was isolated as a solid (6 mg, 7%). ¹H NMR (CDCl₃): 9.73 (brs,1H), 8.88 (d, J=7.8 Hz, 1H), 8.77 (brs, 1H), 7.89 (m, 1H), 7.19–7.59 (m,6H), 7.02 (s, 1H), 4.05 (s, 3H).

EXAMPLE 2054-(1,5,6-Trimethyl-benzimidazol-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 1,5,6-trimethyl-4-aminobenzimidazole (50 mg, 0.288 mmol) similar toExample 185 and was isolated as a solid (5 mg, 6%). ¹H NMR (CDCl₃): 9.36(ddd, J=7.8, 3.0, 1,2 Hz, 1H), 9.68 (s, 1H), 9.01 (ddd, J=5.7, 2.7, 1.2Hz, 1H), 8.87 (s, 1H), 8.46 (dd, J=8.4, 6.0 Hz, 1H), 8.04 (s, 1H), 7.71(s, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 2.62 (s, 3H), 2.24 (s, 3H), 2.21(s, 3H).

EXAMPLE 2064-(2,6-Dimethoxypyridin-3-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 3-amino-2,6-dimethoxypyridine (44 mg, 0.288 mmol) similar to Example180 and was isolated as a yellow solid (15 mg, 20%). ¹H NMR (CDCl₃):9.62 (brs, 1H), 8.72–8.67 (m, 2H), 7.42 (dd, J=8.1, 5.4 Hz, 1H), 7.09(s, 1H), 6.75 (s, 1H), 6.43 (d, J=8.7 Hz, 1H), 4.08 (s, 3H), 4.02 (s,3H).

EXAMPLE 2074-(2-Methoxy-pyridin-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 5-amino-2-methoxypyridine (35 mg, 0.288 mmol) similar to Example 180and was isolated as a solid (30 mg, 45%). ¹H NMR (CDCl₃): 9.65 (brs,1H), 8.72–8.69 (m, 2H), 8.26 (d, J=2.7 Hz, 1H), 7.71 (d, J=6.9 Hz, 1H),7.44–7.40 (m, 2H), 6.86 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 3.98 (s, 3H).

EXAMPLE 2084-(4,6-Dimethoxy-pyrimidin-2-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 2-amino-4,6-dimethoxypyrimidine (27 mg, 0.288 mmol) similar toExample 190 and was isolated as a solid. ¹H NMR (CDCl₃): 9.65 (brs, 1H),8.71–8.70 (m, 2H), 7.54 (brs, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 7.25(s, 1H), 7.04 (s, 1H), 6.07 (t, J=5.4 Hz, 1H).

EXAMPLE 2094-(5-Chloro-2-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 4-amino-5-chloro-2-methylpyrimidine (42 mg, 0.288 mmol) similar toExample 190 and was isolated as a solid. ¹H NMR (CDCl₃): 9.58 (d, J=1.5Hz, 1H), 8.72–8.65 (m, 2H), 7.42 (dd, J=6, 5.1 Hz, 1H), 6.70 (s, 1H),5.32 (s, 2H), 1.70 (s, 3H).

EXAMPLE 2104-(2-Hydroxy-5-methyl-pyrimidin-4-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 4-amino-2-hydroxy-5-methylpyrimidine (36 mg, 0.288 mmol) similar toExample 190 and was isolated as a solid. ¹H NMR (CDCl₃): 9.47 (brs, 1H),8.59–8.54 (m, 2H), 7.28 (dd, J=8.1, 5.1 Hz, 1H), 6.59 (s, 1H), 5.18 (s,2H), 1.70 (s, 3H).

EXAMPLE 2114-(1,3,4-Triazol-1-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 1-amino-1,3,4-triazole (24 mg, 0.288 mmol) similar to Example 190and was isolated as a solid. ¹H NMR (CDCl₃): 9.61 (brs, 1H), 8.71–8.66(m, 4H), 7.41 (m, 2H), 6.69 (s, 1H), 5.18 (s, 2H).

EXAMPLE 2124-(Indol-4-ylamino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 4-aminoindole (37 mg, 0.288 mmol) similar to Example 180 and wasisolated as a solid (55 mg, 80%). ¹H NMR (CDCl₃): 8.76 (brs, 1H), 8.58(d, J=8.1 Hz, 1H), 7.93 (t, J=7.5 Hz, 1H), 7.51–7.39 (m, 3H), 7.28–7.16(m, 3H), 6.94 (s, 1H), 6.45 (s, 1H).

EXAMPLE 2134-(2-Methyl-indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine

The title compound was prepared from4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol)and 5-amino-2-methylindole (41 mg, 0.288 mmol) similar to Example 190and was isolated as a solid. ¹H NMR (CDCl₃): 9.66 (s, 1H), 8.75–8.72 (m,2H), 8.08 (s, 1H), 7.46–7.34 (m, 4H), 7.10 (d, J=8.4 Hz, 1H), 6.78 (s,1H), 6.45 (s, 1H).

EXAMPLE 2144-(2-Chloro-5-methoxy-anilino)-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidinehydrochloride

a. 2-Amidinopyrimidine: A solution of 2-cyanopyrimidine (4 g, 38.06mmol) in 7N ammonia in methanol (300 ml) was stirred at room temperaturefor 48 h. The mixture was rotary evaporated to dryness. The residue waswashed with hexane, filtered, and dried under vacuo to give a pale whitesolid (3.5 g, 76%). ¹H NMR (DMSO-d₆): 8.96 (d, J=4.8 Hz, 2H), 7.63 (t,J=4.8 Hz, 1H), 7.10 (bs, 3H).

b. 2-(2-Pyrimidinyl)-6-trifluoromethylpyrimidin-4-ol: To a stirringsolution of ethanolic sodium ethoxide (100 mg of sodium ethoxide in 20ml of ethanol) was added 2-amidinopyrimidine (500 mg, 4.09 mmol) andethyl 4,4,4-trifluoroacetoacetate (897 ul, 6.14 mmol). The mixture wasrefluxed for 24 h. The mixture was cooled to room temperature and thenrotary evaporated to dryness. To the residue was added water (40 ml) andthe mixture was extracted with chloroform (2×60 ml). The chloroformsolution was dried over anhydrous sodium sulfate and then concentratedin vacuo. The residue was purified by column chromatography to give theproduct as a yellow solid (350 mg, 35%). ¹H NMR (CDCl₃): 11.21 (s, 1H),9.04 (d, J=5.1 Hz, 2H), 7.58 (t, J=5.1 Hz, 1H), 6.98 (s, 1H).

c. 4-Chloro-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidine: A solution of2-(2-pyrimidinyl)-6-trifluoromethylpyrimidin-4-ol (135 mg, 0.557 mmol)in phosphorus oxychloride (3 ml) was refluxed for 3 h. The mixture wascooled to room temperature and then rotary evaporated to leave a brownoil. The oil was extracted with ethyl acetate (75 ml), and the extractswere washed with water (2×20 ml), and dried over anhydrous sodiumsulfate. The ethyl acetate solution was rotary evaporated to dryness togive a yellow solid (120 mg, 83%). ¹H NMR (CDCl₃): 9.08 (d, J=4.5 Hz,2H), 7.83 (s, 1H), 7.51 (t, J=4.5 Hz, 1H).

d.4-(2-Chloro-5-methoxy-anilino)-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidinehydrochloride: A mixture of4-chloro-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.288 mmol) inwater:ethanol (2:1, 10 ml) was refluxed for 48 h. The mixture was cooledto room temperature and basified with aqueous 2N NaOH to pH 10–12. Theresulting precipitate was collected by filtration and purified by columnchromatography to give a yellow solid (21 mg, 28%). ¹H NMR (CDCl₃): 9.01(d, J=4.8 Hz, 2H), 7.71 (s, 1H), 7.67 (s, 1H), 7.44 (t, J=4.8 Hz, 1H),7.36 (d, J=9.3 Hz, 1H), 7.09 (s, 1H), 6.75 (dd, J=3.0, 9.0 Hz, 1H), 3.86(s, 3H).

EXAMPLE 2154-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(t-butyl)pyrimidine

a. 4-Chloro-2-(3-pyridinyl)-6-(t-butyl)pyrimidine: The title compoundwas prepared from 6-tert-butyl-2-pyridin-3-yl-pyrimidin-4-ol (400 mg,1.75 mmol) and phosphorus oxychloride (10 ml) similar to Example 214cand isolated as a tan solid (333 mg, 77%). ¹H NMR (CDCl₃): 9.68 (d,J=1.5 Hz, 1H), 8.80–8.76 (m, 1H), 8.73 (dd, J=1.5, 4.8 Hz, 1H),7.49–7.44 (m, 1H), 7.28 (s, 1H), 1.41 (s, 9H).

b. 4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(t-butyl)pyrimidine:The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(tert-butyl)pyrimidine (50 mg, 0.202 mmol)and 2-chloro-5-methoxyaniline hydrochloride (59 mg, 0.303 mmol) similarto Example 117 and isolated as a yellow oil (12 mg, 15%). ¹H NMR(CDCl₃): 9.70 (s, 1H), 8.75–8.68 (m, 2H), 8.13 (d, J=2.7 Hz, 1H),7.42–7.39 (m, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.11 (s, 1H), 6.65 (s, 1H),6.60 (dd, J=3.0, 8.7 Hz, 1H), 3.87 (s, 3H), 1.39 (s, 9H).

EXAMPLE 2164-(3-Methoxyanilino)-2-(2-piperidinyl)-6-(trifluoromethyl)pyrimidine

To a solution of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50mg, 0.144 mmol) in methanol (20 ml) was added concentrated hydrochloricacid (200 ul). The mixture was hydrogenated over palladium (5 wt % onactivated carbon) at 50 psi for 6 h. The mixture was filtered throughCelite. The filtrate was rotary evaporated to dryness and purified bycolumn chromatography to give a brown oil (3 mg, 6%). ¹H NMR (CDCl₃):7.83 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 6.90–6.85 (m, 3H), 6.77 (dd,J=1.8, 7.8 Hz, 1H), 3.90 (dd, J=3.0, 10.5 Hz, 1H), 3.81 (s, 3H), 3.29(d, J=11.4 Hz, 1H), 2.88–2.80 (m, 2H), 2.25 (d, J=10.5 Hz, 1H), 1.92 (s,1H), 1.69–1.56 (m, 4H).

EXAMPLE 2174-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl-N-oxide)-6-(trifluoromethyl)pyrimidine

To a stirring solution of4-(2-chloro-5-methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine(50 mg, 0.131 mmol) in dichloromethane (5 ml) was addedm-chloroperbenzoic acid (23 mg, 0.131 mmol). The mixture was stirred atroom temperature for 30 minutes and then rotary evaporated to dryness.The residue was purified by column chromatography to give a white solid(19 mg, 36%). ¹H NMR (CDCl₃): 8.35 (d, J=7.5 Hz, 2H), 8.28 (d, J=7.5 Hz,2H), 7.64 (d, J=2.4 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.30 (s, 1H), 6.94(s, 1H), 6.76 (dd, J=3.0, 9.0 Hz, 1H), 3.85 (s, 3H).

EXAMPLE 2184-(4-Chloro-2-methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 4-chloro-2-methoxy-5-methylaniline (50 mg, 0.289 mmol) similarto Example 117 and isolated as a tan solid (26 mg, 34%). ¹H NMR (CDCl₃):9.65–9.63 (m, 1H), 8.75–8.70 (m, 2H), 8.18 (s, 1H), 7.46–7.41 (m, 1H),7.36 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H).

EXAMPLE 2194-(2,4,5-Trimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

a. 2,4,5-Trimethylphenylamine: A solution of 5-nitropseudocumene (400mg, 2.42 mmol) in methanol (30 ml) was hydrogenated over palladium (5 wt% on activated carbon) at 50 psi for 3 h. The mixture was filteredthrough Celite. The filtrate was rotary evaporated to leave a lightpurple residue (246 mg, 75%). ¹H NMR (CDCl₃): 6.82 (s, 1H), 6.50 (s,1H), 3.42 (s, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

b.4-(2,4,5-Trimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine:The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) 2,4,5-trimethylphenylamine (39 mg, 0.289 mmol) similar to Example117 and isolated as a yellow solid (21 mg, 30%). ¹H NMR (CDCl₃): 9.70(d, J=1.8 Hz, 1H), 8.73–8.70 (m, 1H), 8.67 (dd, J=1.5, 4.8 Hz, 1H), 7.65(s, 1H), 7.42–7.38 (m, 1H), 7.11 (s, 1H), 7.10 (s, 1H), 6.51 (s, 1H),2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).

EXAMPLE 2204-(2,4-Dichloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine

The title compound was prepared from a mixture of4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193mmol) and 5-amino-2,4-dichlorobenzenol (51 mg, 0.289 mmol) similar toExample 117 and isolated as a white solid (24 mg, 31%). ¹H NMR(DMSO-d₆): 10.80 (s, 1H), 9.90 (s, 1H), 9.39–9.38 (m, 1H), 8.75–8.72 (m,1H), 8.57–8.53 (m, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.59–7.55 (m, 1H),7.31 (s, 1H).

EXAMPLE 221 Identification of4-(3-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine andAnalogs as Caspase Cascade Activators and Inducers of Apoptosis in SolidTumor Cells

Human breast cancer cell lines T-47D and ZR-75-1 were grown according tomedia component mixtures designated by American Type CultureCollection+10% FCS (Invitrogen Corporation, Life Technologies division),in a 5% CO₂-95% humidity incubator at 37° C. T-47D and ZR-75-1 cellswere maintained at a cell density between 50 and 80% confluency at acell density of 0.1 to 0.6×10⁶ cells/ml. Cells were harvested at 600×gand resuspended at 0.65×10⁶ cells/ml into appropriate media+10% FCS. Analiquot of 45 μl of cells was added to a well of a 96-well microtiterplate containing 2.5 μl of a 10% DMSO in RPMI-1640 media solutioncontaining 0.16 to 100 μM of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine orother test compound (0.016 to 10 μM final). An aliquot of 22.5 μl ofcells was added to a well of a 384-well microtiter plate containing 2.5μl of a 10% DMSO in RPMI-1640 media solution without test compound asthe control sample. The samples were mixed by agitation and thenincubated at 37° C. for 48 h in a 5% CO₂-95% humidity incubator. Afterincubation, the samples were removed from the incubator and 25 μl of asolution containing 14 μM of N-(Ac-DEVD)-N′-ethoxycarbonyl-R110fluorogenic substrate (Cytovia, Inc.; WO99/18856), 20% sucrose (Sigma),20 mM DTT (Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2(Sigma), and 500 μg/ml lysolecithin (Calbiochem) was added. The sampleswere mixed by agitation and incubated at room temperature. Using afluorescent plate reader (Model SpectraMax Gemini, Molecular Devices),an initial reading (T=0) was made approximately 1–2 min after additionof the substrate solution, employing excitation at 485 nm and emissionat 530 nm, to determine the background fluorescence of the controlsample. After the 3 h incubation, the samples were read for fluorescenceas above (T=3 h).

Calculation:

The Relative Fluorescence Unit values (RFU) were used to calculate thesample readings as follows:RFU _((T=3h))−Control RFU _((T=0))=Net RFU _((T=3h))

The activity of caspase cascade activation was determined by the ratioof the net RFU value for4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine orother test compound to that of control samples. The EC₅₀ (nM) wasdetermined by a sigmoidal dose-response calculation (Prism 2.0, GraphPadSoftware Inc.). The caspase activity (Ratio) and potency (EC₅₀) aresummarized in Table I:

TABLE I CASPASE ACTIVITY AND POTENCY T47 T47 ZR ZR Compd Ratio EC50Ratio EC50 # Structure 48 hr (nM) 48 hr (nM) A

29.3 433 3.6 140 19

16.7 471 8.9 214 41

7.5 521 1.6 >5000 74

16.4 364 13.1 326 73

1.6 >5000 2.6 10000 131

1.2 >5000 1.2 >5000 164

1.3 >5000 1.3 >5000 125

4.4 3467 8.1 2239 163

1.1 >5000 1.6 >5000 75

16.3 2292 7.8 3276 81

12.7 5052 5.0 5497 44

1.6 >5000 1.9 >5000 45

21.6 329 17.3 387 16

19.5 288 3.3 292 109

3.9 1495 3.6 2594 110

8.9 576 11.6 648 111

4.0 1421 3.9 2569 112

3.3 1860 2.9 2371 113

4.4 1426 4.1 2733 114

3.6 2539 3.7 2800 15

2.5 >5000 2.7 >5000 18

1.9 >5000 7.8 4901 46

1.5 >5000 1.4 >5000 20

1.6 >5000 1.1 >5000 160

1.0 >5000 1.4 >5000 104

1.1 >5000 1.7 >5000 200

1.2 >5000 1.4 >5000 69

14.2 382 10.9 127 92

16.8 363 12.4 285 156

1.7 >5000 4.1 2261 96

1.4 >5000 4.9 2759 93

2.0 >5000 8.2 2032 97

14.5 659 6.7 717 60

1.8 >5000 1.4 >5000 62

1.6 >5000 1.3 >5000 65

1.7 >5000 1.7 >5000 61

1.8 >5000 1.2 >5000 59

1.6 >5000 1.1 >5000 58

1.5 >5000 1.1 >5000 66

1.2 >5000 0.9 >5000 67

1.5 >5000 1.2 >5000 63

8.9 18 9.6 43 38

8.8 19 12.4 69 42

5.8 43 2.5 145 76

8.5 <150 ND^(a) ND 102

8.0 512 7.4 701 85

1.7 >5000 6.7 2834 51

11 29 5.9 56 99

11.1 34 12.0 50 55

8.4 21 7.1 18 80

8.5 64 5.9 243 180

15.1 637 8.7 698 50

10 172 5.3 322 95

11.6 113 8.6 148 82

15.3 254 ND ND 54

10.5 99 5.9 101 127

10.3 279 5.3 550 188

3.6 429 9.3 271 117

11.3 138 6.3 276 118

8.8 34 9.9 31 194

11.7 107 ND ND 106

9.0 183 2.4 982 107

8.0 63 5.3 123 21

15.5 <156 12.0 <156 53

20.4 115 6.6 599 52

20.9 108 7.2 98 190

19.3 29 16.7 32 198

3.3 419 1.8 >5000 162

11.3 272 7.3 360 87

19.2 <75 16.9 <75 88

9.8 2315 8.0 1216 89

8.7 2737 9.8 1603 126

12.0 222 5.9 353 123

21.2 763 15.8 725 116

13.7 71 8.8 73 196

11.3 527 ND ND 68

20.9 247 17.9 130 115

14.2 112 11.6 59 91

11.7 1442 8.8 788 120

8.2 2694 4.5 2397 183

17.3 82 11.5 75 161

10.7 79 5.1 86 122

11.1 44 10.1 192 195

8.4 20 ND ND 121

11.2 480 9.9 380 128

1.4 >5000 1.5 >5000 124

19.9 720 16.3 688 176

4.5 149 1.9 >5000 179

10.8 1474 1.3 >5000 108

0.9 >5000 2.4 4367 22

1.9 >5000 3.5 6049 130

11.3 295 9.7 167 134

16.5 807 1.5 >5000 133

16.8 1286 4.5 354 157

6.6 43 6.4 197 201

15.7 333 4.8 173 166

8.0 870 3.3 532 206

6.9 802 2.9 583 158

9.5 509 6.0 133 203

10.7 843 3.4 2627 212

5.8 3114 6.1 2781 213

14.1 2685 9.9 1768 147

13.3 335 8.4 204 148

13.8 412 8.4 243 149

16.0 75 10.0 46 150

11.0 135 9.7 133 151

12.0 388 8.6 276 152

14.6 35 8.6 212 153

15.7 43 9.3 146 154

6.1 22 7.9 14 ^(a)ND, not determined.Thus, 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine(Compound A) and related compounds are identified as potent caspasecascade activators and inducer of apoptosis in solid tumor cells.

EXAMPLE 222 Identification of4-(3-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine asAntineoplastic Compound that Inhibits Cell Proliferation (GI₅₀)

T-47D cells were grown and harvested as in Example 221. An aliquot of 90μl of cells (2.2×10⁴ cells/ml) was added to a well of a 96-wellmicrotiter plate containing 10 μl of a 10% DMSO in RPMI-1640 mediasolution containing 1 nM to 100 μM of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (0.1nM to 10 μM final). An aliquot of 90 μl of cells was added to a well ofa 96-well microtiter plate containing 10 μl of a 10% DMSO in RPMI-1640media solution without compound as the control sample for maximal cellproliferation (A_(Max)). The samples were mixed by agitation and thenincubated at 37° C. for 48 h in a 5% CO₂-95% humidity incubator. Afterincubation, the samples were removed from the incubator and 20 μl ofCellTiter 96 AQ_(UEOUS) One Solution Cell Proliferation™ reagent(Promega) was added. The samples were mixed by agitation and incubatedat 37° C. for 2–4 h in a 5% CO₂-95% humidity incubator. Using anabsorbance plate reader (Model 1420 Wallac Instruments), an initialreading (T=0) was made approximately 1–2 min after addition of thesolution, employing absorbance at 490 nm. This determines the possiblebackground absorbance of the test compounds. No absorbance for4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine wasfound at 490 nm. After the 2–4 h incubation, the samples were read forabsorbance as above (A_(Test)).

Baseline for GI₅₀ (dose for 50% inhibition of cell proliferation) ofinitial cell numbers were determined by adding an aliquot of 90 μl ofcells or 90 μl of media, respectively, to wells of a 96-well microtiterplate containing 10 μl of a 10% DMSO in RPMI-1640 media solution. Thesamples were mixed by agitation and then incubated at 37° C. for 0.5 hin a 5% CO₂-95% humidity incubator. After incubation, the samples wereremoved from the incubator and 20 μl of CellTiter 96 AQ_(UEOUS) OneSolution Cell Proliferation™ reagent (Promega) was added. The sampleswere mixed by agitation and incubated at 37° C. for 2–4 h in a 5%CO₂-95% humidity incubator. Absorbance was read as above, (A_(Start))defining absorbance for initial cell number used as baseline in GI₅₀determinations.

Calculation:

GI₅₀ (dose for 50% inhibition of cell proliferation) is theconcentration where [(A_(Test)−A_(Start))/(A_(Max)−A_(Start))]=0.5

The GI₅₀ (nM) are summarized in Table II

TABLE II GI₅₀ in T-47D Cancer Cells Compound A Cell lines GI50 (nM)T-47D 30Thus, 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine(Compound A) is identified as antineoplastic compound that inhibits cellproliferation.

EXAMPLE 223 Identification of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine asAntineoplastic Compound that Selectively Inhibits the Proliferation ofBreast Cancer Cells (G_(I50))

T-47D, ZR-75-1, MX-1, SK-Br-3, MCF-7, MDA-MB-435 (all breast cancer celllines), Panc-1 (pancreatic cancer cell line), MES-SA (sarcoma cellline), and PC-3 (prostate cancer cell line) cells were grown accordingto the conditions recommended by American Type Culture Collection. SW620(colorectal cancer cell line), and P388 (mouse leukemia cell line) weregrown according to the conditions provided by the National CancerInstitute. The cell proliferation assay and the calculations of GI₅₀Swere performed as in Example 222 and the results were summarized inTables III and IV.

TABLE III GI50 in human breast cancer cell lines. Cell Line T47D ZR 75-1MCF-7 MDA-MB-435 SK—Br-3 GI₅₀(nM) 30 100 100 4500 60

TABLE IV GI50 in non-breast cancer cell lines. Cell Line PC-3 Panc-1SW620 P388 MES-SA GI₅₀(nM) >10,000 >10,000 >10,000 >10,000 >10,000Thus, 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinewas identified as antineoplastic compound that selectively inhibits thegrowth of human breast cancer cells.

EXAMPLE 224 Treatment with4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine Leadsto Cell Cycle Arrest and Apoptosis in T-47D Cells

T-47D, a breast cancer cell line, was maintained and harvested asdescribed in Example 221. 5×10⁵ Cells were treated with 0.2 μM of4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine for48 h at 37° C. As a control, cells were also incubated with equivalentamount of solvent (DMSO). Cells were harvested at 1,200 rpm and thentransferred to 12×75 mm polystyrene tubes. Cells were then resuspendedin 500 μl of 1% Na Citrate, 0.1% Triton X-100, and 50 μg/ml of propidiumiodide and incubated at room temperature for 30 min followed by flowcytometer analysis. All flow cytometry analyses were performed onFACScalibur (Becton Dickinson) using Cell Quest analysis software. Thex-axis plotted the amount of fluorescence and the y-axis is plotted thenumber of cells with the indicated fluorescence. The T-47D control cellpopulation profile is seen in FIG. 1A and the increase in G2/M DNAcontent cells that is seen when treated with4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine at0.2 μM is seen in FIG. 1B. An increase in the sub-diploid DNA content ofcells (FIG. 1) is also seen to increase from 2% to 25% with compoundtreatment. The sub-diploid amount of DNA is indicative of apoptoticcells which have undergone DNA degradation or fragmentation.

EXAMPLE 2254-(3-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidineInhibit the Clonogenic Survival of T47D and MX-1, Solid Tumor Cell Lines

T47D and MX-1 cells were grown according to the conditions accordingconditions recommended by American Type Culture Collection. In a well ofa 96 well plate, 30,000 cells were seeded and treated with testedcompound at the indicated concentrations for 48 hr in a 5% CO₂-95%humidity incubator at 37° C. Control wells were treated with the sameamount of solvent (DMSO) as the compound samples. After the 48 htreatment, the supernatant was removed to a sterile culture tube and thewells washed with phosphate buffered saline, and the adherent cellstrypsinized for 5 min. The trypsinzed cells were added to the culturesupernatant, cells were collected (1,200 rpm, 10 min), washed withphosphate buffered saline, and resuspended in fresh media. The cellswere counted for trypan blue negative cells, and the cells diluted withfresh media to 1,000 cells/ml. To a well of a 24-well plate, 0.1 ml ofthe cell suspension was added along with 1 ml of fresh media (cellsuspensions were passed through a 22G needle several times just beforeplating to form single cell suspensions). Plates are incubated in a 5%CO₂-95% humidity incubator at 37° C. for 7–10 days. Colonies are countedwhen the sizes reached greater than 50 cells per colony. Cells arewashed with phosphate buffered saline, fixed with 100% methanol for 15min, and then stained with 0.5% gentian violet for 15 min. Colonies arerinsed with water and the colonies counted and the fraction survivingexpressed as the percentage of the number of control colonies.

The results showed that a 48 hr treatment with4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidineinhibited the ability of T47D and MX-1 cells to proliferate and theircolony forming ability with an IC₅₀ of about 100 and 300 nM,respectively.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1. A method of treating breast cancer, lung cancer or colon cancer,comprising administering to an animal in need of such treatment aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ar₁is optionally substituted pyridinyl, pyridinyl N-oxide, pyrazinyl,pyrimidinyl or phenyl and Ar₂ is optionally substituted pyridinyl,indolyl or:

A is C—R₂; R₁ and R₂ are independently hydrogen, halo, haloalkyl, aryl,fused aryl, carbocyclic, morpholinyl, pyridinyl, alkyl, alkenyl,alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, nitro,amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy,alkoxyalkyl, aryloxy, arylalkoxy, haloalkoxy, carbonylamido oralkylthiol; R₃ is hydrogen, optionally substituted alkyl or optionallysubstituted cycloalkyl; and R₉–R₁₃ are independently hydrogen, halo,haloalkyl, aryl, fused aryl, carbocyclic, alkyl, alkenyl, alkynyl,arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, hydroxyalkyl,nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy,aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol.2. The method of claim 1, wherein said animal is a mammal.
 3. The methodof claim 1, wherein R₃ is hydrogen.
 4. The method of claim 1, whereinsaid compound has the Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R₁–R₃,and Ar₂ are as defined in claim 1; B is N or C—R₄; D is N or C—R₅; E isN or C—R₆; F is N or C—R₇; G is N or C—R₈; and R₄–R₈ are independentlyhydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, C₁₋₁₀ alkyl,alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl,hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy,azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamidoor alkylthiol; provided that not more than two of B, D, E, F or G are N.5. The method of claim 4, wherein R₁ is optionally substituted alkyl orhaloalkyl.
 6. The method of claim 4, wherein Ar₂ is:


7. The method of claim 4, wherein B is N.
 8. The method of claim 1,wherein said compound is selected from the group consisting of:4-(3-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Fluoroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,5-Dichloroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,4-Difluoroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Methylanilino)-2-phenyl-6-methylpyrimidine;4-(4-Methoxyanilino)-2-(2-hydroxyphenyl)-6-methylpyrimidine;4-(4-(Trifluoromethoxy)anilino)-2-(pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,5-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-(Trifluoromethyl)anilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-(Trifluoromethyl)anilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Fluoroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,4-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Chloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,4-Dichloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Chloroanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Fluoroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Fluoroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-(Trifluoromethyl)anilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Chloroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Chloroanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;4-(3-Chloroanilino)-2-(2-pyridinyl)-6-(methoxymethyl)pyrimidine;4-(4-(Trifluoromethoxy)anilino)-2-(2-pyridinyl)-6-t-butylpyrimidine;4-(4-Methoxyanilino)-2-(2-pyridinyl)-6-t-butylpyrimidine;4-(3-Methoxyanilino)-2-phenyl-6-chloropyrimidine;4-(3-Methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3-Fluoroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3-Methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(4-Methoxyanilino)-2-(3-methylphenyl)-6-(methoxymethyl)pyrimidine;4-(2,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3-Dimethylaminoanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3-Isopropylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;4-(3-Methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(3-Methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;4-(3,4-Dimethoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-phenyl-6-(trifluoromethyl)pyrimidine;4-(2-Methoxy-5-phenoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Fluoro-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Methyl-5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(3-Ethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Ethylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Methylmercaptoanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(3-Hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;4-(3,5-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)-pyrimidinehydrochloride;4-(2,5-Diethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Carboxyl-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2-Chloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,6-Dimethylanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(2,5-Dimethylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2-Methoxy-5-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Hydroxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Hydroxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Cyano-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,5-Dimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,5-Dimethoxyanhlino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2-Chloro-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Methoxy-5-trifluoromethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine;4-(5-Bromo-2-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Bromo-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-[3-Methyl-5-(trifluoromethyl)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Chloro-2-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Chloro-2,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2,4-Dichloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Acetyl-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Methyl-5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;N-[4-Methyl-3-(2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;4-Methyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;6-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]nicotinamide;N-[4-Methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]-4-morpholino-benzamide;4-Chloro-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;4-Methoxy-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;4-Chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide;4-(2,5-Dimethyl-4-hydroxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2,5-Dimethyl-4-hydroxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Chloro-2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(4,5-Dimethoxy-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(3-Trifluoromethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(4,5-Dimethoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(4-Chloro-2,5-dimethoxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2-Hydroxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,5-Dimethoxyanilino)-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine;4-(5-Chloro-2-methoxyanilino)-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine;6-Methyl-4-(3-phenoxyanilino)-2-(2-pyridinyl)pyrimidine;4-(3-Chloroanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3,4-Dimethoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(4-Fluoro-3-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3-Isopropoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine;4-(3,4-Dimethoxyanilino)-6-trifluoromethyl-2-(2-pyridinyl)pyrimidine;4-(5-Chloro-2-methoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(5-Hydroxy-2-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Chloro-5-hydroxyanilino)-2-(2-pyridinyl)-6-trifluormethylpyrimidine;4-(2-Methoxy-5-methylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Hydroxy-5-isopropylanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;4-(3,5-Dimethoxyanilino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;4-(2,5-Dimethyl-4-hydroxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Cyano-4,5-dimethoxyanilino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(3-pyridinyl)-6-(t-butyl)pyrimidine;4-(4-Chloro-2-methoxy-5-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(2,4,5-Trimethylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;and4-(2,4-Dichloro-5-hydroxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine.9. The method of claim 1, wherein said compound is selected from thegroup consisting of: 4-(3-Methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(2-Methoxy-5-methylanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(2,5-Dimethylanilino)-2,6-di(2-pyridinyl)pyrimidine;4-(Indol-4-ylamino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(Indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine;4-(2,6-Dimethoxypyridin-3-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Methoxy-pyridin-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(Indol-4-ylamino)-2-(2-pyridinyl)-6-trifluoromethylpyrimidine;4-(2-Methyl-indol-5-ylamino)-2-(3-pyridinyl)-6-trifluoromethylpyrimidine;4-(3-Methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;4-(2,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;4-(3,4-Dimethoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;4-(5-Methoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;4-(3-Hydroxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2,5-Dimethyl-4-hydroxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(4-Chloro-2,5-dimethoxyanilino)-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(4,5-Dimethoxy-2-methylanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidinehydrochloride;4-(2-Methoxy-5-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Methoxy-2-nitroanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(3,5-Dimethoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Carboxy-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(2-Methoxy-5-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Hydroxy-2-methylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(2-Chloro-5-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(2,5-Dimethylanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Chloro-2-methoxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Chloro-2-hydroxyanilino)-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine;4-(5-Hydroxy-2-isopropylanilino)-2-(2-pyrazinyl)-6-trifluoromethypyrimidine;4-(2-Chloro-5-methoxyanilino)-2-(4-pyridinyl-N-oxide)-6-(trifluoromethyl)pyrimidine;and4-(2-Chloro-5-methoxy-anilino)-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidinehydrochloride.
 10. The method of claim 1, wherein said animal is amammal.
 11. A method for the treatment of drug resistant breast cancer,lung cancer or colon cancer, comprising administering to an animal inneed of such treatment an effective amount of a compound of the FormulaI:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ar₁is optionally substituted pyridinyl, pyridinyl N-oxide, pyrazinyl,pyrimidinyl or phenyl and Ar₂ is optionally substituted pyridinyl,indolyl or:

A is —C—R₂; R₁ and R₂ are independently hydrogen, halo, haloalkyl, aryl,fused aryl, carbocyclic, morpholinyl pyridinyl C₁₋₁₀ alkyl, alkenyl,alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, nitro,amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy,alkoxyalkyl, aryloxy, arylalkoxy, haloalkoxy, carbonylamido oralkylthiol; R₃ is hydrogen, optionally substituted alkyl or optionallysubstituted cycloalkyl; and R₉–R₁₃ are independently hydrogen, halo,haloalkyl, aryl, fused aryl, carbocyclic, alkyl, alkenyl, alkynyl,arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, hydroxyalkyl,nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy,aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol.12. The method of claim 11, wherein said animal is a mammal.
 13. Themethod of claim 1 or 11, additionally comprising administering at leastone known cancer chemotherapeutic agent, or a pharmaceuticallyacceptable salt of said agent.
 14. The method of claim 13, wherein saidknown cancer therapeutic agent is selected from the group consisting ofbusulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine,paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide,5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine,ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil,cyclophosphamide, ifosfamide, vincristine, mitoguazone, epirubicin,aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine,octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan® andalanosine.
 15. The method of claim 1 or 11, additionally comprisingtreating said animal with radiation-therapy.
 16. The method of claim 1or 11, wherein said compound is administered after surgical treatment ofsaid animal for cancer.
 17. A method of treating breast cancer, lungcancer or colon cancer, comprising administering to an animal in need ofsuch treatment an effective amount of a compound selected from the groupconsisting of:4-(3-Methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;4-(2,5-Dimethoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1-3-thiazol-4-yl)pyrimidine;4-(2-Chloro-5-methoxyanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;4-(5-Methoxy-2-methylanilino)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine;4-(3,4-Methylenedioxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,4-Methylenedioxyanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,4-Methylenedioxyanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-[2-Methyl-5-(carboxymethylester)anilino]-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine;4-(3,4-Methylenedioxyanilino)-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine;and4-(3-Methoxyanilino)-2-(2-piperidinyl)-6-(trifluoromethyl)pyrimidine.18. The method of claim 1, wherein said cancer is lung carcinoma. 19.The method of claim 1, wherein said cancer is colon carcinoma.
 20. Themethod of claim 1, wherein said cancer is breast carcinoma.